Substituted benzimidazoles and imidazo-[4,5]-pyridines

ABSTRACT

2-Aryl substituted benzimidazoles and imidazo[4,5]pyridines are disclosed as inhibitors of Cds1 and useful as adjuvants to chemotherapy or radiation therapy in the treatment of cancer.

This application is a divisional of application Ser. No. 10/825,823,filed Apr. 16, 2004, now U.S. Pat. No. 7,132,440, which in turn claimsthe benefit of U.S. provisional application Ser. No. 60/463,542, filedApr. 17, 2003.

FIELD OF THE INVENTION

The present invention relates to substituted benzimidazole andimidazo-[4,5]-pyridine compounds, compositions containing them, andmethods of using them.

BACKGROUND OF THE INVENTION

The maintenance of an intact genome is of crucial importance to everyorganism. The individual cell in a multicellular eukaryotic organismpossesses sophisticated and intricate mechanisms to properly respond toDNA damage. Such mechanisms repair damaged DNA or trigger programmedcell death (apoptosis). In response to DNA damage, checkpoint kinasesare thought to be intimately involved in these processes. These kinasesare activated by upstream proteins, such as ATM (ataxia-telangiectasiamutated) and ATR (ataxia-telangiectasia mutated and rad3-related), andin turn trigger cell cycle arrest by inhibition of proteins such asCdc25A or Cdc25C. The checkpoint kinases May also, modulate the activityof other proteins that are thought to be involved in DNA repair andprogrammed cell death. Examples of such proteins are BRC1 and p53.

The checkpoint kinase Cds1 (in man also known as Chk2) is conserved fromyeast to man. A human homolog of the Schizosaccharomyces pombe Cds1 genehas been described (Tominaga, K. et al. J. Biol. Chem. 1999,274(44):31463-31467; Matsouka, S. et al. Science 1998, 282:1893-1897;Blasina, A. et al. Curr. Biol. 1999, 9(1):1-10). Human Cds1 was rapidlyactivated by phosphorylation in response to DNA damage in both normalcells and in p53-deficient cancer cells. High levels of hCds1 wereobserved in p53-deficient cells. In human cells Cds1 has been implicatedin the regulation by phosphorylation of proteins such as p53, BRCA1,Cdc25A, and Cdc25C (See: Lee, J.-S. et al. Nature 2000, 404:201-204;Falck, J. et al. Nature 2001, 410:842-847; and Buscemi, G. et al. Mol.Cell. Biol. 2001, 21(15):5214-5221). As described below, inhibition ofCds1 offers two strategies for improving the effectiveness ofDNA-damaging cancer treatments.

Cancer cells are often deficient in the mechanisms responsible formaintaining an intact genome. In particular, they have often lost properp53 function, which generally correlates with the progression of a tumorto a more aggressive state, such as the progression from a preinvasiveto invasive stage of colon cancer, or from a low grade to a high gradeastrocytoma. Between 30% and 70% of all subtypes of tumors have a pointmutation in one of the two p53 gene copies and have lost the otherallele. P53-deficient cells are generally more resistant to radiation.It is thought that the lack of initiation of programmed cell death incancer cells may render such cells less sensitive to DNA-damaging cancertreatments. The transcription factor p53 is of importance not only forthe initiation of programmed cell death, but also in cell cycle arrest.Loss of p53 function may therefore leave cancer cells with limitedprotection against insult to the genome. Further disruption of DNAdamage repair and cell cycle arrest by inhibition of kinases such asCds1 could then render cancer cells unable to survive after DNA damage.Therefore inhibition of Cds1 could, by removing the remaining componentsof DNA damage repair, render the cancer cells more susceptible totreatments such as chemical DNA-damaging agents or ionizing radiation.

Normal cells, on the other hand, have an intact p53 system, and willoften undergo apoptosis in response to DNA-damaging treatments at a muchlower dose than that required to kill cancer cells. Therefore, in suchsituations, normal cells will be at a disadvantage compared to cancercells, and cancer treatments often have to be discontinued due toserious side effects caused by loss of normal cells before the cancerhas been eradicated. Inhibition of Cds1, which would prevent this kinasefrom phosphorylating and thereby stabilizing p53, could thereforeprotect normal cells from the effects of ionizing radiation orDNA-damaging chemotherapeutics while still allowing these agents to beeffective against p53-deficient cancer cells. This would have the effectof increasing the therapeutic potential of these agents. This view issupported by studies of mice deficient in Cds1 (See: Hirao, A. et al.Mol. Cell. Biol. 2002, 22(18):6521-6532; Takai, H. et al. EMBO J. 2002,21(19):5195-5205; WO 01/98465 A1 Chugai Seiyaku Kabushiki Kaisha, Dec.27, 2001). These animals showed increased resistance to the apoptosiscaused by ionizing radiation over their wild-type counterparts. Forexample, it was shown that these animals were protected from apoptosisof intestinal cells, hair-follicle cells, cells of the CNS, and thyrhuscells relative to their wild-type counterparts when treated withionizing radiation. Cds1 knockout animals also showed increased survivalwhen exposed to ionizing radiation. It is therefore logical to assumethat chemical inhibitors of Cds1 would have therapeutic potential in theprotection of patients from the deleterious side effects of radiation orDNA-damaging chemotherapeutics.

Additional examples of cell cycle checkpoint modulators in developmentinclude UCN-01 (CAS-112953-11-4), UCN-02, KW-2401, NSC-638850 (KyowaHakko/National Cancer Institute) and SB-218078 (CAS 135897-06-2)(SmithKline Beecham).

Additional relevant publications include DE 0148431 (T 7570), WO01/21771′ A2, WO 02/072090; A1, WO 03/011219 A2, and White, A. W. et al.J. Med. Chem. 2000, 43(22):4084-4097.

It is an object of the present invention to provide a Cds1-inhibitingadjuvant for use with ionizing radiation in the treatment of cancers.

It is another object of the present invention to provide aCds1-inhibiting adjuvant for use with DNA-damaging chemotherapeutics inthe treatment of cancers.

It is still another object of the present invention to provide aCds1-inhibiting adjuvant for use with ionizing radiation and/orDNA-damaging chemotherapeutics that promotes the death of cancer cellsdamaged by such radiation or chemotherapeutics.

It is yet another object of the present invention to provide aCds1-inhibiting adjuvant for use with ionizing radiation and/orDNA-damaging chemotherapeutics that prevents apoptosis of healthy cellsdamaged by such radiation or chemotherapeutics.

It is also an object of the present invention to provide aCds1-inhibiting adjuvant for use with ionizing radiation and/orDNA-damaging chemotherapeutics that both promotes in a patient the deathof cancer cells and prevents the apoptosis of healthy cells damaged bysuch radiation or chemotherapeutics.

It is also another object of the present invention to provide aCds1-inhibiting adjuvant for use with ionizing radiation and/orDNA-damaging chemotherapeutics in the treatment of p53-deficient cancercells.

It is an additional object of the present invention to provide a Cds1inhibiting adjuvant for use with ionizing radiation and/or DNA-damagingchemotherapeutics that both promotes in a patient the death ofp53-deficient cancer cells and prevents the apoptosis of healthy cellsdamaged by such radiation or chemotherapeutics.

It is an object of the present invention to provide a method for thetreatment of cancer in a patient comprising exposing the cancer toionizing radiation and administering a Cds1-inhibiting adjuvant.

It is another object of the present invention to provide a method forthe treatment of cancer in a patient comprising administering aDNA-damaging chemotherapeutic and a Cds1-inhibiting adjuvant.

It is still another object of the present invention to provide a methodto promote in a patient the death of cancer cells damaged by exposure toionizing radiation and/or by administration of a DNA-damagingchemotherapeutic comprising the step of administering a Cds1-inhibitingadjuvant in conjunction with such therapies.

It is yet another object of the present invention to provide a method toprevent in a patient the apoptosis of healthy cells damaged by exposureto ionizing radiation and/or by administration of a DNA-damagingchemotherapeutic comprising the step of administering a Cds1-inhibitingadjuvant in conjunction with such therapies.

It is also an object of the present invention to provide a method toboth promote in a patient the death of cancer cells and prevent theapoptosis of healthy cells damaged by exposure to ionizing radiationand/or by administration of a DNA-damaging chemotherapeutic comprisingthe step of administering a Cds1-inhibiting adjuvant in conjunction withsuch therapies.

It is also another object of the present invention to provide a methodfor the treatment of p53-deficient cancer cells in a patient comprisingexposing the cancer cells to ionizing radiation and/or administering aDNA-damaging chemotherapeutic and administering a Cds1-inhibitingadjuvant.

It is an additional object of the present invention to provide a methodto both promote in a patient the death of p53-deficient cancer cells andto prevent the apoptosis of healthy cells damaged by exposure toionizing radiation and/or by administration of a DNA-damagingchemotherapeutic comprising the step of administering a Cds1-inhibitingadjuvant in conjunction with such therapies.

SUMMARY OF THE INVENTION

The present invention features compounds of formula (I):

wherein

-   W is —COOH, —(CO)NH₂, or —(SO₂)NH₂;-   Q is N or CH;-   R_(a) and R_(b) are independently selected from —H and halogen;-   R_(c) is absent or is independently selected from the group    consisting of —OH, —CF₃, —C₁₋₄alkyl, —OC₁₋₄alkyl, —NO₂ and halo;-   Z is selected from the group consisting of    -   a) >C═O, >C═CHR_(f), >CR_(d)R_(d), >CF₂, >CR_(d)OR_(e),        >C(OR_(d))OR_(e),    -   b) >C(R_(d))NR_(d)R_(g),    -   c) —SO₂NR_(d)C(R_(h))₂—,

-   -   where A is fused at the b or c faces, at a face of A which        contains two carbon atoms, which is saturated or unsaturated,

-   -   where A is fused at the b or c faces, at a face of A which        contains two carbon atoms, which is saturated or unsaturated,    -   d) >NC₁₋₄alkyl, where the alkyl is optionally substituted with a        substituent selected from the group consisting of —NH₂,        —NHC₁₋₄alkyl; —N(C₁₋₄alkyl)₂, —CONH₂, —CONHC₁₋₄alkyl,        —CON(C₁₋₄alkyl)₂, —COOH, —COOC₁₋₄alkyl, —OH and —OC₁₋₄alkyl;

-   R_(d) is independently selected from the group consisting of —H and    —C₁₋₄alkyl;

-   R_(e) is independently selected from the group consisting of —H and    optionally mono- or di-substituted —C₁₋₄alkyl, where the substituent    is independently selected from the group consisting of —NH₂,    —NHC₁₋₄alkyl, —N(C₁₋₄alkyl)₂, —CONH₂, —CONHC₁₋₄alkyl,    —CON(C₁₋₄alkyl)₂, —COOH, —COOC₁₋₄alkyl, —CN, —OH and —OC₁₋₄alkyl;

-   alternatively, R_(d) and R_(e) may be taken together with their    atoms of attachment to form a 5 to 8 membered heterocyclic ring,    with the heterocyclic ring having 0 or 1 unsaturated bonds, having    0, 1 or 2 carbon members which is a carbonyl, having 0 or 1    additional heteroatom members separated from an atom of attachment    by at least one carbon member and selected from O, S, —N═, >NH or    >NC₁₋₄alkyl and having a maximum of two heteroatom ring members;

-   R_(f) is independently selected from the group consisting of —H,    —CONH₂, —CONHC₁₋₄alkyl, —CON(C₁₋₄alkyl)₂, —COOH, —COOC₁₋₄alkyl and    optionally mono- or di-substituted C₁₋₄alkyl, where the substituent    is independently selected from the group consisting of —NH₂,    —NHC₁₋₄alkyl, —N(C₁₋₄alkyl)₂, —CONH₂, —CONHC₁₋₄alkyl,    —CON(C₁₋₄alkyl)₂, —COOH, —COOC₁₋₄alkyl, —CN, —OH and —OC₁₋₄alkyl;

-   R_(g) is independently selected from the group consisting of —H and    optionally mono- or di-substituted —C₁₋₄alkyl, where the substituent    is independently selected from the group consisting of —NH₂,    —NHC₁₋₄alkyl, —N(C₁₋₄alkyl)₂, —CONH₂, —CONHC₁₋₄alkyl,    —CON(C₁₋₄alkyl)₂, —COOH, —COOC₁₋₄alkyl, —CN, —OH and —OC₁₋₄alkyl;

-   alternatively, R_(d) and R_(g) may be taken together with their    nitrogen of common attachment to form a 5 to 8 membered heterocyclic    ring, with the heterocyclic ring having 0 or 1 unsaturated bonds,    having 0, 1 or 2 carbon members which is a carbonyl and having 0 or    1 additional heteroatom members separated from the atom of common    attachment by at least one carbon member and selected from O, S,    —N═, >NH or >NC₁₋₄alkyl;

-   R_(h) is independently selected from the group consisting of —H, and    optionally mono- or di-substituted C₁₋₄alkyl, where the substituent    is independently selected from the group consisting of —NH₂,    —NHC₁₋₄alkyl, —N(C₁₋₄alkyl)₂, —CN, —OH and —OC₁₋₄alkyl; or,    alternatively, R_(h) is —CH₂CH₂— or —CH₂CH₂CH₂—, optionally    substituted with R_(i), which is bonded to a carbon of A adjacent to    the carbon of Z attachment, forming a five- or six-membered    carbocyclic ring;

-   R_(i) is independently selected from the group consisting of —H,    —OH, —OC₁₋₄alkyl and optionally mono- or di-substituted C₁₋₄alkyl,    where the substituent is independently selected from the group    consisting of —NH₂, —NHC₁₋₄alkyl, —N(C₁₋₄alkyl)₂, —CONH₂,    —CONHC₁₋₄alkyl, —CON(C₁₋₄alkyl)₂, —COOH, —COOC₁₋₄alkyl, —CN, —OH and    —OC₁₋₄alkyl;

-   A is selected from the group consisting of:    -   a) phenyl, optionally mono-, di- or tri-substituted with R_(p);        -   R_(p) is selected from the group consisting of —OH,            —C₁₋₆alkyl, —OC₁₋₆alkyl, —C₃₋₆cycloalkyl, —OC₃₋₆cycloalkyl,            —CN, —NO₂, —N(R_(y))R_(z) (wherein R_(y) and R_(z) are            independently selected from —H or —C₁₋₆alkyl, or may be            taken together with the nitrogen of attachment to form an            otherwise aliphatic hydrocarbon ring, said ring having 5 to            7 members, optionally having one carbon replaced with >O,            ═N—, >NH or >N(C₁₋₄alkyl) and optionally having one or two            unsaturated bonds in the ring), —(C═O)N(R_(y))R_(z),            —(N—R_(t))COR_(t) (wherein R_(t) is independently —H or            —C₁₋₆alkyl), —(N—R_(t))SO₂C₁₋₆alkyl, —(C═O)C₁₋₆alkyl,            —(S═(O)_(n))—C₁₋₆alkyl (wherein n is selected from 0, 1 or            2), —SO₂N(R_(y))R_(z), —SCF₃, halo, —CF₃, —OCF₃, —COOH,            —C₁₋₆alkylCOOH, —COOC₁₋₆alkyl and —C₁₋₆alkylCOOC₁₋₆alkyl;    -   b) phenyl, attached at two adjacent ring members to a C₃₋₅alkyl        moiety to form a fused 5 to 7 membered ring, said fused ring        optionally having a second unsaturated bond, said fused ring        optionally having one or two members replaced with ═N—, >O, >NH        or >N(C₁₋₄alkyl) except that no such replacement is permitted        where the fused ring is 5 membered and has a second unsaturated        bond, and said fused ring optionally having one carbon member        replaced with >C═O, the fused rings optionally mono-, di- or        tri-substituted with R_(p);    -   c) a monocyclic aromatic hydrocarbon group having six ring        carbon atoms, having a carbon atom which is the point of        attachment, having one or two carbon atoms replaced by N, and        optionally mono- or di-substituted with R_(p);    -   d) a monocyclic aromatic hydrocarbon group having six ring        carbon atoms, having a carbon atom which is the point of        attachment, having zero, one or two carbon atoms replaced by N,        and having attachment at two adjacent carbon ring members to a        three membered hydrocarbon moiety to form a fused five membered        aromatic ring, which moiety has one carbon atom replaced        by >O, >S, >NH or >N(C₁₋₄alkyl) and which moiety has up to one        additional carbon atom optionally replaced by N, the fused rings        optionally mono-, di- or tri-substituted with R_(p);    -   e) a monocyclic aromatic hydrocarbon group having six ring        carbon atoms, having a carbon atom which is the point of        attachment, having zero, one or two carbon atoms replaced by N,        and having attachment at two adjacent carbon ring members to a        four membered hydrocarbon moiety to form a fused six membered        aromatic ring, which moiety has zero, one or two carbon atoms        replaced by N, the fused rings optionally mono-, di- or        tri-substituted with R_(p);    -   f) a monocyclic aromatic hydrocarbon group having five ring        carbon atoms, having a carbon atom which is the point of        attachment, having one carbon atom replaced by >O, >S, >NH or        >N(C₁₋₄alkyl), having up to one additional carbon atom        optionally replaced by N, and optionally mono- or di-substituted        with R_(p);    -   g) a monocyclic aromatic hydrocarbon group having five ring        carbon atoms, having a carbon atom which is the point of        attachment, having one carbon atom replaced by >O, >S, >NH or        >N(C₁₋₄alkyl), and having attachment at two adjacent carbon ring        members to a four membered hydrocarbon moiety to form a fused        six membered aromatic ring, which moiety has zero, one or two        carbon atoms replaced by N, the fused rings optionally mono-,        di- or tri-substituted with R_(p);    -   h) a 4-7 membered aliphatic or heterocyclic ring said        heterocyclic ring having a carbon atom which is the point of        attachment, having 0 or 1 heteroatom members selected from O, S,        —N═, >NH or >NR_(p), having 0, 1 or 2 unsaturated bonds, having        0, 1 or 2 carbon members which is a carbonyl and having 0, 1 or        2 substituents R_(p),    -   i) a benzo fused 4-7 membered aliphatic or heterocyclic ring        said heterocyclic ring having a carbon atom which is the point        of attachment, having 0 or 1 additional heteroatom members        selected from O, S, —N═, >NH or >NR_(p), having 0 or 1        additional unsaturated bonds, having 0, 1 or 2 carbon members        which is a carbonyl, having 0, 1, 2, or 3 halo substituents on        the benzene ring only and having 0, 1 or 2 substituents R_(p),        and enantiomers, diastereomers and pharmaceutically acceptable        salts, esters or amides thereof.

In one aspect, the invention provides a method for treating a subjectsuffering from cancer, said method comprising administering to saidsubject a therapeutically effective amount of a pharmaceuticalcomposition comprising a compound of formula (I). According to oneaspect, the cancer is p-53 deficient.

In another aspect, the invention provides a method for treating asubject suffering from a p53-deficient tumor, said method comprising (a)administering to said subject a therapeutically effective amount of apharmaceutical composition comprising a compound of formula (I) and (b)damaging the DNA of said subject, for example, by administration of aDNA-damaging treatment or agent, such as ionizing radiation or achemical agent that causes DNA damage. In one aspect, the DNA damagingtreatment is provided such that administration of the compound offormula (I) provides effective serum levels of the compound of formula(I) during the treatment and 12 hours to 5 days thereafter, for example,1-2 days thereafter. In a further aspect, the method of treatmentfurther includes administration of one or more additional anti-canceragents, to provide in total three or four (or more) agents, to beadministered in an effective anti-cancer amount. Multiple or combinationtherapies may allow use of lower amounts of one or more of theindividual agents, when compared with monotherapy, and thereby reducingthe incidence or degree of adverse effects.

Examples of such DNA-damaging chemical agents are compounds that causeDNA strand breaks directly such as bleomycin. DNA damage may also becaused by alkylating agents such as hexamethylamine, busulfan,carboplatin, carmustine, cisplatinum, cyclophosphamide, dacarbazine,ifosfamide, lomustine, mechlorethamine, melphalan, procarbazine,streptozocin or thiotepa, or combinations thereof. DNA damage may alsobe caused indirectly by topoisomerase inhibitors such as etoposide,irinotecan, teniposide, topotecan, and doxorubicin or by antimetabolitessuch as cladribine, cytarabine, floxuridine, 5-fluorouracil,gemcitibine, hydroxyurea, mercaptopurine, methotreaxate, pentostatin,thioguanine, and triemtrexate. Enhancement of DNA damaging effects andimproved therapeutic responses can be obtained by combining anticanceragents such as those exemplified above.

A third aspect of the invention provides the use, or the use for themanufacture of a medicament, of a disclosed compound for treating atumor, in particular, a p53 deficient tumor, and more in particular, atumor selected from lung, prostate, colon, brain, head and neck, andbreast. Other tumors include tumors of the stomach, liver, and ovary. Ap-53 deficient tumor is a tumor wherein the functions mediated by p53are lacking or suppressed due to genetic mutations in the gene encodingp53 or through deficiencies or disregulation of proteins that modulatep53 expression levels and function. Examples of such proteins are MDM2and p14(ARF). A further aspect of the invention includes the treatmentof a late-stage, e.g., stage 3 or stage 4, tumor.

The invention also features anti-cancer pharmaceutical compositionscomprising as active ingredient an effective amount of a disclosedcompound of formula (I), and a pharmaceutically acceptable carrier. Theactive ingredient can be formulated in any manner suitable for theparticular tumor, including aerosol, oral, injectable and topicalformulations, and time-release formulations thereof.

Additional features and advantages of the invention will become apparentfrom the detailed description and examples below, and the appendedclaims.

DETAILED DESCRIPTION OF THE INVENTION

Preferably, W is —(CO)NH₂.

Preferably, Q is CH.

Preferably, R_(a) and R_(b) are —H, —Cl or —F.

More preferably, R_(a) is —H and R_(b) is —Cl or —F.

Most preferably, R_(a) and R_(b) are —H.

Preferably, R_(c) is absent or is selected from the group consisting of—OH, —CH₃, —CH₂CH₃, —F, —Cl, —Br, —I, —CF₃ and —OCH₃.

Most preferably, R_(c) is selected from the group consisting of —F, —Cl,—CH and —OCH₃.

Most preferably, R_(c) is absent.

Preferably, R_(d) is selected from the group consisting of —H, —CH₃,—CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂, —CH₂CH₂CH₂CH₃, —CH(CH₃)CH₂CH₃ and—C(CH₃)₃.

Most preferably, R_(d) is selected from the group consisting of —H, —CH₃and —CH₂CH₃.

Preferably, R_(e) is selected from the group consisting of —H, —CH₃,—CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂, —CH₂CH₂CH₂CH₃, —CH(CH₃)CH₂CH₃ and—C(CH₃)₃, where the alkyl members are optionally mono- ordi-substituted. Preferably the optional substituent is independentlyselected from the group consisting of —NH₂, —NHCH₃, —NHCH₂CH₃, —N(CH₃)₂,—N(CH₂CH₃)₂, —CONH₂, —CONHCH₃, —CONHCH₂CH₃, —CON(CH₃)₂, —CON(CH₂CH₃)₂,—COOH, —COOCH₃, —COOCH₂CH₃, —CN, —OH, —OCH₃, —OCH₂CH₃ and —OCH₂CH₂CH₃.

Most preferably, R_(e) is selected from the group consisting of —H, —CH₃and —CH₂CH₃, where the alkyl members are optionally mono- ordi-substituted. Most preferably the optional substituent isindependently selected from the group consisting of —NH₂, —NHCH₃,—N(CH₃)₂, —CONH₂; —CONHCH₃, —CON(CH₃)₂, —COOH, —COOCH₃, —CN, —OH and—OCH₃.

Most preferably, R_(e) is —H or —CH₃.

Preferably, R_(d) and R_(e) taken together with their atoms ofattachment form a heterocyclic ring selected from the group consistingof

said heterocyclic ring having 0 or 1 unsaturated bonds and having 0, 1or 2 carbon members which is a carbonyl, where Y is selected from O, S,—N═, >NH or >NC₁₋₄alkyl.

More preferably, R_(d) and R_(e) taken together with their atoms ofattachment form a heterocyclic ring selected from the group consistingof

where Y is selected from O, >NH or >NC₁₋₄alkyl.

More preferably, R_(d) and R_(e) taken together with their atoms ofattachment form a heterocyclic ring selected from the group consistingof

Most preferably, R_(d) and R_(e) taken together with their atoms ofattachment form a heterocyclic ring selected from the group consistingof

Preferably, R_(f) is selected from the group consisting of —H, —CONH₂,—CONHCH₃, —CONHCH₂CH₃, —CON(CH₃)₂, —CON(CH₂CH₃)₂, —COOH, —COOCH₃,—COOCH₂CH₃, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂, —CH₂CH₂CH₂CH₃,—CH(CH₃)CH₂CH₃ and —C(CH₃)₃, where the alkyl members are optionallymono- or di-substituted. Preferably, the optional substituents areindependently selected from the group consisting of —NH₂, —NHCH₃,—NHCH₂CH₃, —N(CH₃)₂, —N(CH₂CH₃)₂, —CONH₂, —CONHCH₃, —CONHCH₂CH₃,—CON(CH₃)₂, —CON(CH₂CH₃)₂, —COOH, —COOCH₃, —COOCH₂CH₃, —CN, —OH, —OCH₃,—OCH₂CH₃ and —OCH₂CH₂CH₃.

More preferably, R_(f) is selected from the group consisting of —H,—CONH₂, —CONHCH₃, —CON(CH₃)₂, —COOH, —COOCH₃, —CH₃ and —CH₂CH₃, wherethe alkyl members are optionally mono- or di-substituted. Mostpreferably, the optional substituent is independently selected from thegroup consisting of —NH₂, —NHCH₃, —N(CH₃)₂, —CONH₂, —CONHCH₃,—CON(CH₃)₂, —COOH, —COOCH₃, —CN, —OH and —OCH₃.

Most preferably, R_(f) is selected from the group consisting of —H and—CH₃.

Preferably, R_(g) is selected from the group consisting of —H, —CH₃,—CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂, —CH₂CH₂CH₂CH₃, —CH(CH₃)CH₂CH₃ and—C(CH₃)₃, where the alkyl moieties are optionally mono- ordi-substituted. Preferably, the optional substituent is independentlyselected from the group consisting of —NH₂, —NHCH₃, —NHCH₂CH₃, —N(CH₃)₂,—N(CH₂CH₃)₂, —CONH₂, —CONHCH₃, —CONHCH₂CH₃, —CON(CH₃)₂, —CON(CH₂CH₃)₂,—COOH, —COOCH₃, —COOCH₂CH₃, —CN, —OH, —OCH₃, —OCH₂CH₃ and —OCH₂CH₂CH₃.

Most preferably, R_(g) is selected from the group consisting of —H, —CH₃and —CH₂CH₃ where the alkyl members are optionally mono- ordi-substituted. Most preferably the optional substituent isindependently selected from the group consisting of —NH₂, —NHCH₃,—N(CH₃)₂, —CONH₂, —CONHCH₃, —CON(CH₃)₂, —COOH, —COOCH₃, —CN, —OH and—OCH₃.

Preferably, R_(d) and R_(g) taken together with their nitrogen ofattachment to form a heterocyclic ring are selected from the groupconsisting of

the heterocyclic ring having 0 or 1 unsaturated bonds and having 0, 1 or2 carbon members which is a carbonyl, where Y is selected from O, S,—N═, >NH or >NC₁₋₄alkyl.

More preferably, R_(d) and R_(g) taken together with their atoms ofattachment to form a heterocyclic ring are selected from the groupconsisting of

where Y is selected from O, S, >NH or >NC₁₋₄alkyl.

Most preferably, R_(d) and R_(g) taken together with their atoms ofattachment to form a heterocyclic ring are selected from the groupconsisting of

where Y is selected from O, S, >NH or >NC₁₋₄alkyl.

Preferably, R_(h) is selected from the group consisting of —H, —CONH₂,—CONHCH₃, —CONHCH₂CH₃, —CON(CH₃)₂, —CON(CH₂CH₃)₂, —COOH, —COOCH₃,—COOCH₂CH₃, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂, —CH₂CH₂CH₂CH₃,—CH(CH₃)CH₂CH₃ and —C(CH₃)₃, where the alkyl members are optionallymono- or di-substituted. Preferably the optional substituent isindependently selected from the group consisting of —NH₂, —NHCH₃,—NHCH₂CH₃, —N(CH₃)₂, —N(CH₂CH₃)₂, —CONH₂, —CONHCH₃, —CONHCH₂CH₃,—CON(CH₃)₂, —CON(CH₂CH₃)₂, —COOH, —COOCH₃, —COOCH₂CH₃, —CN, —OH, —OCH₃,—OCH₂CH₃ and —OCH₂CH₂CH₃. Alternatively, R_(h) is —CH₂CH₂— or—CH₂CH₂CH₂—, which is bonded to a carbon of A adjacent to the carbon ofZ attachment, forming a five- or six-membered carbocyclic ring.

More preferably, R_(h) is selected from the group consisting of —H,—CONH₂, —CONHCH₃, —CON(CH₃)₂, —COOH, —COOCH₃, —CH₃ and —CH₂CH₃, wherethe alkyl members are optionally mono- or di-substituted. Mostpreferably, the optional substituent is independently selected from thegroup consisting of —NH₂, —NHCH₃, —N(CH₃)₂, —CONH₂, —CONHCH₃,—CON(CH₃)₂, —COOH, —COOCH₃, —CN, —OH and —OCH₃. Alternatively, R_(h) is—CH₂CH₂— or —CH₂CH₂CH₂—, which taken together with A forms indanyl or1,2,3,4-tetrahydronaphthalenyl.

Most preferably, R_(h) is selected from the group consisting of —H, —CH₃and —CH₂CH₃.

Preferably, R_(i) is selected from the group consisting of —H, —OH,—OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃—, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂,—CH₂CH₂CH₂CH₃; —CH(CH₃)CH₂CH₃ and —C(CH₃)₃, where the directly attachedalkyl members are optionally mono- or di-substituted. Preferably theoptional substituent is independently selected from the group consistingof —NH₂, —NHCH₃, —NHCH₂CH₃, —N(CH₃)₂, —N(CH₂CH₃)₂, —CONH₂, —CONHCH₃,—CONHCH₂CH₃, —CON(CH₃)₂, —COOH, —COOCH₃, —COOCH₂CH₃, —CN, —OH, —OCH₃,—OCH₂CH₃ and —OCH₂CH₂CH₃.

Most preferably, R_(i) is selected from the group consisting of —H, —OH,—OCH₃, —CH₃ and —CH₂CH₃; where the directly attached alkyl members areoptionally mono- or di-substituted. Most preferably, the optionalsubstituent is independently selected from the group consisting of —NH₂,—NHCH₃, —N(CH₃)₂, —CONH₂, —CONHCH₃, —CON(CH₃)₂, —COOH, —COOCH₃, —CN, —OHand —OCH₃.

Preferably Z is selected from the group consisting of

-   -   a) >C═O, >C═CH₂, >CH₂, >CHC₁₋₄alkyl, >CF₂, >CHOH, >CHOC₁₋₄alkyl,

-   -   b) >CHNR_(d)R_(g);    -   c) —SO₂NR_(d)CH(R_(h))—,

-   -   where A is fused at the c face, at a face of A which contains        two carbon atoms, which is saturated or unsaturated,

-   -   where A is fused at the c face, at a face of A which contains        two carbon atoms, which is saturated or unsaturated,    -   d) >NCH₃, >NCH₂CH₃, >NCH₂CH₂CH₃, >NCH(CH₃)₂, >NCH₂CH₂CH₂CH₃, and        >NCH(CH₃)CH₂CH₃, where the alkyl attached to >N is optionally        substituted with a substituent selected from the group        consisting of —NH₂, —NHCH₃, —NHCH₂CH₃, —N(CH₃)₂, —N(CH₂CH₃)₂,        —CONH₂, —CONHCH₃, —CONHCH₂CH₃, —CON(CH₃)₂, —CON(CH₂CH₃)₂, —COOH,        —COOCH₃, —COOCH₂CH₃, —OH, —OCH₃, —OCH₂CH₃ and —OCH₂CH₂CH₃.

Most preferably, Z is selected from the group consisting of

-   -   a) >C═O, >C═CHR_(f), >CHR_(d), >CF₂, >CHOR_(e).

-   -   b)>CHNHR_(g), >CHNCH₃R_(g),

-   -   where Y is selected from O, S, —N═, >NH or >NC₁₋₄alkyl;    -   c) —SO₂NHCH₂—, —SO₂NCH₃CH₂—,

-   -   where A is fused at the c face, at a face of A which contains        two carbon atoms, which is saturated or unsaturated,

-   -   where A is fused at the c face, at a face of A which contains        two carbon atoms, which is saturated or unsaturated,    -   d) >NCH₃, >NCH₂CH₃, >NCH₂CH₂CH₃, >NCH(CH₃)₂, where the alkyl        attached to >N is optionally substituted with a substituent        selected from the group consisting of —NH₂, —NHCH₃, —NHCH₂CH₃,        —N(CH₃)₂, —N(CH₂CH₃)₂, —CONH₂, —CONHCH₃, —CONHCH₂CH₃,        —CON(CH₃)₂, —CON(CH₂CH₃)₂, —COOH, —COOCH₃, —COOCH₂CH₃, —OH,        —OCH₃, —OCH₂CH₃ and —OCH₂CH₂CH₃.

Preferably, A, optionally substituted with R_(p), is selected from thegroup consisting of:

-   -   a) phenyl,    -   b) tetralin-5, 6, 7 or 8-yl, chroman-5, 6, 7 or 8-yl,        benzo-1,2-pyran-5,6,7 8-yl, benzo-2,3-pyron-5, 6, 7 or 8-yl,        coumarin-5, 6, 7 or 8-yl, isocoumarin-5, 6, 7 or 8-yl,        benzo-1,3,2-benzoxazin-5, 6, 7 or 8-yl, benzo-1,4-dioxan-5, 6, 7        or 8-yl, 1,2,3,4-tetrahydroquinolin-5, 6, 7 or 8-yl,        1,2,3,4-tetrahydroquinoxalin-5, 6, 7 or 8-yl, thiochroman-5, 6,        7 or 8-yl, 2,3-dihydrobenzo[1,4]dithiin-5, 6, 7 or 8-yl,        1,2,3,4-tetrahydroisoquinolin-5, 6, 7 or 8-yl, indene-4, 5, 6,        or 7-yl, 1,2,3,4-tetrahydronapth-5, 6, 7, or 8 yl,        1,2-dihydroisoindolo-4, 5, 6, or 7-yl, 2,3-dihydroindene-4, 5,        6, or 7-yl, benzo-1,3-dioxol-4, 5, 6 or 7-yl,        2,3-dihydroindol-4, 5, 6 or 7-yl, 2,3-dihydrobenzofuran-4, 5, 6        or 7-yl, 2,3-dihydrobenzothiophen-4, 5, 6 or 7-yl,        2,3-dihydrobenzoimidazol-4, 5, 6 or 7-yl,    -   c) pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl,    -   d) benzoxazol-4, 5, 6 or 7-yl, benzothiophen-4, 5, 6 or 7-yl,        benzofuran-4, 5, 6 or 7-yl, indol-4, 5, 6 or 7-yl,        benzthiazol-4, 5, 6 or 7-yl, benzimidazo-4, 5, 6 or 7-yl,        indazol-4, 5, 6 or 7-yl, 1H-pyrrolo[2,3-b]pyridin-4, 5 or 6-yl,        1H-pyrrolo[3,2-c]pyridin-4, 6 or 7-yl,        1H-pyrrolo[2,3-c]pyridin-4, 5 or 7-yl,        1H-pyrrolo[3,2-b]pyridin-5, 6 or 7-yl, purin-2-yl,    -   e) isoquinolin-5, 6, 7 or 8-yl, quinolin-5, 6, 7 or 8-yl,        quinoxalin-5, 6, 7 or 8-yl, quinazolin-5, 6, 7 or 8-yl,        naphthyridinyl,    -   f) furanyl, oxazolyl, isoxazolyl, thiophenyl, thiazolyl,        isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, and    -   g) benzoxazol-2-yl, benzothiophen-2 or 3-yl, benzofuran-2 or        3-yl, indol-2 or 3yl, benzthiazol-2-yl, benzimidazo-2-yl,        indazol-3-yl, 1H-pyrrolo[2,3-b]pyridin-2 or 3-yl,        1H-pyrrolo[3,2-c]pyridin-2 or 3-yl, 1H-pyrrolo[2,3-c]pyridin-2        or 3-yl, 1H-pyrrolo[3,2-b]pyridin-2 or 3-yl, purin-8-yl.

More preferably, A, optionally substituted with R_(p), is selected fromthe group consisting of:

-   -   a) phenyl,    -   b) coumarin-5, 6, 7 or 8-yl, benzo-1,4-dioxan-5, 6, 7 or 8-yl,        1,2,3,4-tetrahydroquinolin-5, 6, 7 or 8-yl,        1,2,3,4-tetrahydroisoquinolin-5, 6, 7 or 8-yl, indene-4, 5, 6,        or 7-yl, 1,2,3,4-tetrahydronapth-5, 6, 7 or 8-yl,        1,2-dihydroisoindolo-4, 5, 6, or 7-yl, 2,3-dihydroindene-4, 5, 6        or 7-yl, benzo-1,3-dioxol-4, 5, 6 or 7-yl, 2,3-dihydroindol-4,        5, 6 or 7-yl, benzo-2,3-dihydrobenzofuran-4, 5, 6 or 7-yl,        2,3-dihydrobenzothiophen-4, 5, 6 or 7-yl,    -   c) pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl,    -   d) benzothiophen-4, 5, 6 or 7-yl, benzofuran-4, 5, 6 or 7-yl,        indol-4, 5, 6 or 7-yl,    -   e) isoquinolin-5, 6, 7 or 8-yl, quinolin-5, 6, 7 or 8-yl,    -   f) furanyl, oxazolyl, isoxazolyl, thiophenyl, thiazolyl,        isothiazolyl, pyrrolyl, imidazol yl, pyrazolyl, and    -   g) benzoxazol-2-yl, benzothiophen-2 or 3-yl, benzofuran-2 or        3-yl, indol-2 or 3-yl.

Most preferably A, optionally substituted with R_(p), is selected fromthe group consisting of: phenyl, benzo-1,4-dioxan-5,6,7 or 8-yl,indene-4,5,6, or 7-yl, 1,2,3,4-tetrahydronapth-5,6,7, or 8-yl,2,3-dihydroindene-4,5,6, or 7-yl, benzo-1,3-dioxol-4,5,6 or 7-yl,2,3-dihydroindol-4,5,6 or 7-yl, 2,3-dihydrobenzofuran-4,5,6 or 7-yl,2,3-dihydrobenzothiophen-4,5,6 or 7-yl, pyridinyl, benzothiophen-4,5,6or 7-yl, benzofuran-4,5,6 or 7-yl, indol-4,5,6 or 7-yl, furanyl,thiophenyl, pyrrolyl, pyrazolyl, and benzothiophen-2 or 3-yl,benzofuran-2 or 3-yl and indol-2 or 3-yl.

A specific A, including the R_(p) substituent, is selected from thegroup consisting of pyridyl, phenyl, naphthyl, quinolinyl, cyclohexyl,4-chloro phenyl, 4-methyl-3-chloro phenyl, 4-chloro-3-trifluoromethylphenyl, 3,4-dichloro phenyl, 3-chloro-4-fluoro phenyl,2-fluoro-5-trifluoromethyl, 4-chloro-3-fluoro phenyl, 3,4-dimethylphenyl, 2-napthyl, 4-trifluoromethyl phenyl, 4-bromo, phenyl,4-fluoro-3-methyl phenyl, 3-chloro phenyl, tetrahydronapthyl,5-chloro-2-methyl phenyl, 3-trifluoromethyl phenyl, 4-methoxy phenyl,4-methyl phenyl, 3,4-dimethyl phenyl, 2-fluoro-3-trifluoromethyl phenyl,2-chloro-4-methyl phenyl, 4-ethyl phenyl, 4-fluoro phenyl, 3,4-dimethoxyphenyl, 3,4-dimethoxy-5-bromo phenyl, 3-(dimethylamino) phenyl, 4-nitrophenyl, 4-cyano phenyl, 2-methoxy-4-methyl phenyl, 4-trifluoromethoxyphenyl, 2-chloro phenyl, 4-morpholino phenyl, 3-chloro phenyl,2,3-dichloro phenyl, benzo[1,3]dioxolyl, benzo[1,4]dioxinyl, 4-aminophenyl, 4-hydroxy phenyl, 4-bromo-3-hydroxy phenyl, 4-chloro-2-hydroxyphenyl, 4-chloro-3-hydroxy phenyl, 2,4-dichloro phenyl,4-bromo-3-methoxy phenyl and 4-iodo phenyl.

A specific A, including the R_(p) substituent, is selected from thegroup consisting of phenyl, 4-chlorophenyl, 4-methylphenyl,4-methoxyphenyl, 2-naphthalenyl, 4-chloro-3-trifluoromethylphenyl,3-bromo-4,5-dimethoxyphenyl, 3,4-dichlorophenyl, 3,4-dimethylphenyl,4-ethylphenyl, benzo[1,3]dioxolyl, 2,3-dihydro-benzo[1,4]dioxinyl,3-quinolinyl, 4-pyridyl, cyclohexyl, 4-tetrahydropyranyl, 2-thiophenyl,6-chloro-benzo[1,3]dioxolyl, 2-chlorophenyl, 2,4-dichlorophenyl,2-methoxyphenyl, 2-methylphenyl, 3-methylphenyl, and 2-furanyl.

Preferably R_(p) is selected from the group consisting of —OH, —CH₃,—CH₂CH₃, —OCH₃, —OCH₂CH₃, —OCH(CH₃)₂, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, —Ocyclopentyl, —Ocyclohexyl, —CN, —NO₂,—C(O)NH₂, —C(O)N(CH₃)₂, —C(O)NH(CH₃), —NHCOCH₃, —NCH₃COCH₃, —NHSO₂CH₃,—NCH₃SO₂CH₃, —C(O)CH₃, —SOCH₃, —SO₂CH₃, —SO₂NH₂, —SO₂NHCH₃, —SO₂N(CH₃)₂,—SCF₃, —F, —Cl, —Br, I, —CF₃, —OCF₃, —COOH, —COOCH₃, —COOCH₂CH₃, —NH₂,—NHCH₃, —N(CH₃)₂, —N(CH₂CH₃)₂, —NCH₃(CH(CH₃)₂), imidazolidin-1-yl,2-imidazolin-1-yl, pyrazolidin-1-yl, piperidin-1-yl, 2- or3-pyrrolin-1-yl, 2-pyrazolinyl, morpholin-4-yl, thiomorpholin-4-yl,piperazin-1-yl, pyrrolidin-1-yl, homopiperidin-1-yl.

Most preferably R_(p) is selected from the group consisting of —H, —OH,—OCH₃, —OCF₃, —CH₃, —CH₂CH₃, —CF₃, —F, —Cl, —Br, —I, —NH₂, —N(CH₃)₂,morpholin-4-yl, —NO₂, —CN, —C(O)NH₂, —COOH, —NHSO₂CH₃, —SO₂NH₂.

The invention features pharmaceutically active, substitutedbenzimidazole compounds as disclosed in the Summary section above.

A. TERMS

The following terms are defined below and by their usage throughout thisdisclosure.

“Alkyl” includes optionally substituted straight chain and branchedhydrocarbons with at least one hydrogen removed to form a radical group.Alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl,t-butyl, 1-methylpropyl, pentyl, isopentyl, sec-pentyl, hexyl, heptyl,octyl, and so on. Alkyl includes cycloalkyl, such as cyclopropyl,cyclobutyl, cyclopentyl, and cyclohexyl.

“Alkenyl” includes optionally substituted straight chain and branchedhydrocarbon radicals as above with at least one carbon-carbon doublebond (sp²). Alkenyls include ethenyl (or vinyl), prop-1-enyl,prop-2-enyl (or allyl), isopropenyl (or 1-methylvinyl), but-1-enyl,but-2-enyl, butadienyls, pentenyls, hexa-2,4-dienyl, and so on.Hydrocarbon radicals having a mixture of double bonds and triple bonds,such as 2-penten-4-ynyl, are grouped as alkynyls herein. Alkenylincludes cycloalkenyl. Cis and trans or (E) and (Z) forms are includedwithin the invention.

“Alkynyl” includes optionally substituted straight chain and branchedhydrocarbon radicals as above with at least one carbon-carbon triplebond (sp). Alkynyls include ethynyl, propynyls, butynyls, and pentynyls.Hydrocarbon radicals having a mixture of double bonds and triple bonds,such as 2-penten-4-ynyl, are grouped as alkynyls herein. Alkynyl doesnot include cycloalkynyl.

“Alkoxy” includes an optionally substituted straight chain or branchedalkyl group with a terminal oxygen linking the alkyl group to the restof the molecule. Alkoxy includes methoxy, ethoxy, propoxy, isopropoxy,butoxy, t-butoxy, pentoxy and so on. “Aminoalkyl”, “thioalkyl”, and“sulfonylalkyl” are analogous to alkoxy, replacing the terminal oxygenatom of alkoxy with, respectively, NH (or NR), S, and SO₂. Heteroalkylincludes alkoxy, aminoalkyl, thioalkyl, and so on.

“Aryl” includes phenyl, naphthyl, biphenylyl, tetrahydronaphthyl, and soon, any of which may be optionally substituted. Aryl also includesarylalkyl groups such as benzyl, phenethyl, and phenylpropyl. Arylincludes a ring system containing an optionally substituted 6-memberedcarbocyclic aromatic ring, said system may be bicyclic, bridge, and/orfused. The system may include rings that are aromatic, or partially orcompletely saturated. Examples of ring systems include indenyl,pentalenyl, 1-4-dihydronaphthyl, indanyl, benzimidazolyl,benzothiophenyl, indolyl, benzofuranyl, isoquinolinyl, and so on:

“Heterocyclyl” includes optionally substituted aromatic and nonaromaticrings having carbon atoms and at least one heteroatom (O, S, N) orheteroatom moiety (SO₂, CO, CONH, COO) in the ring. Unless otherwiseindicated, a heterocyclic radical may have a valence connecting it tothe rest of the molecule through a carbon atom, such as 3-furyl or2-imidazolyl, or through a heteroatom, such as N-piperidyl or1-pyrazolyl. Preferably a monocyclic heterocyclyl has between 4 and 7ring atoms, or between 5 and 6 ring atoms; there may be between 1 and 5heteroatoms or heteroatom moieties in the ring, and preferably between 1and 3. A heterocyclyl may be saturated, unsaturated, aromatic (e.g.,heteroaryl), nonaromatic, or fused.

Heterocyclyl also includes fused, e.g., bicyclic, rings, such as thoseoptionally condensed with an optionally substituted carbocyclic orheterocyclic five or six-membered aromatic ring. For example,“heteroaryl” includes an optionally substituted six-memberedheteroaromatic-ring containing 1, 2 or 3 nitrogen atoms condensed withan optionally substituted five- or six-membered carbocyclic orheterocyclic aromatic ring. Said heterocyclic five- or six-memberedaromatic ring condensed with the said five- or six-membered aromaticring may contain 1, 2 or 3 nitrogen atoms where it is a six-memberedring, or 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulfurwhere it is a five-membered ring.

Examples of heterocyclyls include thiazolyl, furyl, pyranyl,isobenzofuranyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl,isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl,isoindolyl, indolyl, indazolyl, purinyl, quinolyl, furazanyl,pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl,pyrazolinyl, piperidyl, piperazinyl, indolinyl, and morpholinyl. Forexample, preferred heterocyclyls or heterocyclic radicals includemorpholinyl, piperazinyl, pyrrolidinyl, pyridyl, cyclohexylimino,cycloheptylimino, and more preferably, piperidyl.

Examples illustrating heteroaryl are thienyl, furanyl, pyrrolyl,imidazolyl, oxazolyl, thiazolyl, benzothienyl, benzofuranyl,benzimidazolyl, benzoxazolyl, benzothiazolyl.

“Acyl” refers to a carbonyl moiety attached to either a hydrogen atom(i.e., a formyl group) or to an optionally substituted alkyl or alkenylchain, or heterocyclyl.

“Halo” or “halogen” includes fluoro, chloro, bromo, and iodo, andspreferably chloro or bromo as a substituent.

“Alkanediyl” or “alkylene” represents straight or branched chainoptionally substituted bivalent alkane radicals such as, for example,methylene, ethylene, propylene, butylene, pentylene or hexylene.

“Alkenediyl” represents, analogous to the above, straight or branchedchain optionally substituted bivalent alkene radicals such as, forexample, propenylene, butenylene, pentenylene or hexenylene. In suchradicals, the carbon atom linking a nitrogen preferably should not beunsaturated.

“Aroyl” refers to a carbonyl moiety attached to an optionallysubstituted aryl or heteroaryl group, wherein aryl and heteroaryl havethe definitions provided above. In particular, benzoyl isphenylcarbonyl.

As defined herein, two radicals, together with the atom(s) to which theyare attached may form an optionally substituted 4- to 7-, 5- to 7-, or a5- to 6-membered ring carbocyclic or heterocyclic ring, which ring maybe saturated, unsaturated or aromatic. Said rings may be as definedabove in the Summary of the Invention section. Particular examples ofsuch rings are as follows in the next section.

“Pharmaceutically acceptable salts, esters, and amides” includecarboxylate salts (e.g., C₁₋₈alkyl, C₃₋₈ cycloalkyl, aryl, C₂₋₁₀heteroaryl, or C₂₋₁₀ non-aromatic heterocyclic) amino acid additionsalts, esters, and amides that are within a reasonable benefit/riskratio, pharmacologically effective and suitable for contact with thetissues of patients without undue toxicity, irritation, or allergicresponse. Representative salts include hydrobromide, hydrochloride,sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate,palmitate, stearate, laurate, borate, benzoate, lactate, phosphate,tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate,mesylate, glucoheptonate, lactiobionate, and laurylsulfonate. These mayinclude alkali metal and alkali earth cations such as sodium, potassium,calcium, and magnesium, as well as non-toxic ammonium, quaternaryammonium, and amine cations such as tetramethyl ammonium, methylamine,trimethylamine, and ethylamine. See example, S. M. Berge, et al.,“Pharmaceutical Salts,” J. Pharm. Sci., 1977, 66:1-19, which isincorporated herein by reference. Representative pharmaceuticallyacceptable amides of the invention include those derived from ammonia,primary C₁₋₆ alkyl amines and secondary di(C₁₋₆ alkyl) amines. Secondaryamines include 5- or 6-membered heterocyclic or heteroaromatic ringmoieties containing at least one nitrogen atom and optionally between 1and 2 additional heteroatoms. Preferred amides are derived from ammonia,C₁₋₃ alkyl primary amines, and di(C₁₋₂ alkyl)amines. Representativepharmaceutically acceptable esters of the invention include C₁₋₇ alkyl,C₅₋₇ cycloalkyl, phenyl, and phenyl(C₁₋₆)alkyl esters. Preferred estersinclude methyl esters.

“Patient” or “subject” includes mammals such as humans and animals(dogs, cats, horses, rats, rabbits, mice, non-human primates) in need ofobservation, experiment, treatment or prevention in connection with therelevant disease or condition. Preferably, the patient or subject is ahuman.

“Composition” includes a product comprising the specified ingredients inthe specified amounts as well as any product that results directly orindirectly from combinations of the specified ingredients in thespecified amounts.

“Therapeutically effective amount” or “effective amount” means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician, which includes alleviation of the symptoms of thecondition or disorder being treated.

Concerning the various radicals in this disclosure and in the claims,three general remarks are made. The first remark concerns valency. Aswith all hydrocarbon radicals, whether saturated, unsaturated oraromatic, and whether or not cyclic, straight chain, or branched, andalso similarly with all heterocyclic radicals, each radical includessubstituted radicals of that type and monovalent, bivalent, andmultivalent radicals as indicated by the context of the claims. Thecontext will indicate that the substituent is an alkylene or hydrocarbonradical with at least two hydrogen atoms removed (bivalent) or morehydrogen atoms removed (multivalent). An example of a bivalent radicallinking two parts of the molecule is Z in formula (I), which links X andA.

Second, radicals or structure fragments as defined herein are understoodto include substituted radicals or structure fragments. Hydrocarbylsinclude monovalent radicals containing carbon and hydrogen such asalkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl (whether aromaticor unsaturated), as well as corresponding divalent radicals such asalkylene, alkenylene, phenylene, and so on. Heterocarbyls includemonovalent and divalent radicals containing carbon, hydrogen, and atleast one heteroatom. Examples of monovalent heterocarbyls include acyl,acyloxy, alkoxyacyl, heterocyclyl, heteroaryl, aroyl, benzoyl,dialkylamino, hydroxyalkyl, and so on. Using “alkyl” as an example,“alkyl” should be understood to include substituted alkyl having one ormore substitutions, such as between 1 and 5, 1 and 3, or 2 and 4substituents. The substituents may be the same (dihydroxy, dimethyl),similar (chlorofluoro), or different (chlorobenzyl- oraminomethyl-substituted). Examples of substituted alkyl includehaloalkyl (such as fluoromethyl, chloromethyl, difluoromethyl,perchloromethyl, 2-bromoethyl, perfluoromethyl, and 3-iodocyclopentyl),hydroxyalkyl (such as hydroxymethyl, hydroxyethyl, 2-hydroxypropyl,aminoalkyl (such as aminomethyl, 2-aminoethyl, 3-aminopropyl, and2-aminopropyl), nitroalkyl, alkylalkyl, and so on. A di(C₁₋₆ alkyl)aminogroup includes independently selected alkyl groups, to form, forexample, methylpropylamino and isopropylmethylamino, in additiondialkylamino groups having two of the same alkyl group such as dimethylamino or diethylamino.

Third, only stable compounds are intended. For example, where there isan NR′R″ group, and R can be an alkenyl group, the double bond is atleast one carbon removed from the nitrogen to avoid enamine formation.Similarly, where a dashed line is an optional sp² bond, if it is absent,the appropriate hydrogen atom(s) is (are) included.

Compounds of the invention are further described in the next section.

B. COMPOUNDS

The invention features the treatment, or inhibition of onset orprogression, of cancer using one or more Cds1 inhibitors as described inthe Summary section.

Preferred compounds are made according to the synthetic methods outlinedin Schemes 1-9, have demonstrated Cds1 inhibitory activity, and areselected from the group consisting of:

EX Compound Name 12-[4-(2-Phenyl-[1,3]dioxolan-2-yl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide; 22-{4-[2-(4-Chloro-phenyl)-[1,3]dioxolan-2-yl]-phenyl}-1H-benzoimidazole-5-carboxylic acid amide; 32-(4-Benzoyl-phenyl)-1H-benzoimidazole-5-carboxylic acid amide; 42-[4-(4-Chloro-benzoyl)-phenyl]-1H-benzoimidazole-5-carboxylic acidamide; 5 2-[4-(4-Methyl-benzoyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide; 62-[4-(4-Methoxy-benzoyl)-phenyl]-1H-benzoimidazole-5-carboxylic acidamide; 72-[4-(Naphthalene-2-carbonyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide; 82-[4-(4-Chloro-3-trifluoromethyl-benzoyl)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide; 92-[4-(3-Bromo-4,5-dimethoxy-benzoyl)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide; 102-[4-(3,4-Dichloro-benzoyl)-phenyl]-1H-benzoimidazole-5-carboxylic acidamide; 112-[4-(3,4-Dimethyl-benzoyl)-phenyl]-1H-benzoimidazole-5-carboxylic acidamide; 12 2-[4-(4-Ethyl-benzoyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide; 132-[4-(Benzo[1,3]dioxole-5-carbonyl)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide; 142-[4-(2,3-Dihydro-benzo[1,4]dioxine-6-carbonyl)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide; 152-[4-(Quinoline-3-carbonyl)-phenyl]-1H-benzoimidazole-5-carboxylic acidamide; 162-[4-(Pyridine-4-carbonyl)-phenyl]-1H-benzoimidazole-5-carboxylic acidamide; 172-(4-Cyclohexanecarbonyl-phenyl)-1H-benzoimidazole-5-carboxylic acidamide; 18 2-[4-(4-Chloro-benzoyl)-phenyl]-1H-benzoimidazole-5-sulfonicacid amide; 192-[4-(Hydroxy-phenyl-methyl)-phenyl]-1H-benzoimidazole-5-carboxylic acidamide; 202-{4-[(4-Chloro-phenyl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide; 212-[4-(Hydroxy-p-tolyl-methyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide; 222-{4-[Hydroxy-(4-methoxy-phenyl)-methyl]-phenyl}-1H-benzoimidazole-5-carboxylic acid amide; 232-[4-(Hydroxy-naphthalen-2-yl-methyl)-phenyl]-1H-benzoimidazole-5carboxylic acid amide; 242-{4-[(4-Chloro-3-trifluoromethyl-phenyl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylic acid amide; 252-{4-[(3-Bromo-4,5-dimethoxy-phenyl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylic acid amide; 262-{4-[(3,4-Dichloro-phenyl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylic acid amide; 272-{4-[(3,4-Dimethyl-phenyl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylic acid amide; 282-{4-[(4-Ethyl-phenyl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylic acid amide; 292-[4-(Benzo[1,3]dioxol-5-yl-hydroxy-methyl)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide; 302-{4-[(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylic acid amide; 312-[4-(Hydroxy-quinolin-3-yl-methyl)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide; 322-[4-(Hydroxy-pyridin-4-yl-methyl)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide; 332-[4-(Cyclohexyl-hydroxy-methyl)-phenyl]-1H-benzoimidazole-5- carboxylicacid amide; 342-[4-(Methoxy-phenyl-methyl)-phenyl]-1H-benzoimidazole-5-carboxylic acidamide; 35 2-[4-(4-Chloro-benzyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide; 362-(4-Naphthalen-2-ylmethyl-phenyl)-1H-benzoimidazole-5-carboxylic acidamide; 372-[4-(3,4-Dimethyl-benzyl)-phenyl]-1H-benzoimidazole-5-carboxylic acidamide; 38 2-[4-(4-Ethyl-benzyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide; 392-[4-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide; 402-(4-Cyclohexylmethyl-phenyl)-1H-benzoimidazole-5-carboxylic acid amide;41 2-{4-[1-(4-Chloro-phenyl)-vinyl]-phenyl}-1H-benzoimidazole-5-carboxylic acid amide; 422-{4-[1-(4-Chloro-phenyl)-ethyl]-phenyl}-1H-benzoimidazole-5- carboxylicacid amide; 432-{4-[(4-Chloro-phenyl)-piperazin-1-yl-methyl]-phenyl}-1H-benzoimidazole-5-carboxylic acid amide; 442-(4-{(4-Chloro-phenyl)-[methyl-(2-methylamino-ethyl)-amino]-methyl}-phenyl)-1H-benzoimidazole-5-carboxylic acid amide; 452-[4-(Methyl-phenyl-amino)-phenyl]-1H-benzoimidazole-5-carboxylic acidamide; 46 2-(4-Benzylsulfamoyl-phenyl)-1H-benzoimidazole-5-carboxylicacid amide; 472-[4-(4-Methyl-benzylsulfamoyl)-phenyl]-1H-benzoimidazole-5- carboxylicacid amide; 482-[4-(4-Methoxy-benzylsulfamoyl)-phenyl]-1H-benzoimidazole-5- carboxylicacid amide; 492-[4-(4-Chloro-benzylsulfamoyl)-phenyl]-1H-benzoimidazole-5- carboxylicacid amide; 502-[4-(3,4-Dichloro-benzylsulfamoyl)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide; 512-[4-(Benzyl-methyl-sulfamoyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide; 522-[4-(Tetrahydro-pyran-4-carbonyl)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide; 532-[4-(Thiophene-2-carbonyl)-phenyl]-1H-benzoimidazole-5-carboxylic acidamide; 542-[4-(6-Chloro-benzo[1,3]dioxole-5-carbonyl)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide; 552-[4-(2-Chloro-benzoyl)-phenyl]-1H-benzoimidazole-5-carboxylic acidamide; 562-[4-(2,4-Dichloro-benzoyl)-phenyl]-1H-benzoimidazole-5-carboxylic acidamide; 572-[4-(2-Methoxy-benzoyl)-phenyl]-1H-benzoimidazole-5-carboxylic acidamide; 58 2-[4-(2-Methyl-benzoyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide; 59 2-{4-[Hydroxy-(tetrahydro-pyran-4-yl)-methyl]-phenyl}-1H-benzoimidazole-5-carboxylic acid amide; 602-[4-(Hydroxy-thiophen-2-yl-methyl)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide; 612-{4-[(6-Chloro-benzo[1,3]dioxol-5-yl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylic acid amide; 622-{4-[(2-Chloro-phenyl)-hydroxy-methyl]-Phenyl}-1H-benzoimidazole-5-carboxylic acid amide; 632-{4-[(2,4-Dichloro-phenyl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylic acid amide; 642-{4-[Hydrory-(2-methoxy-phenyl)-methyl]-phenyl}-1H-benzoimidazole-5-carboxylic acid amide; 652-[4-(Hydroxy-o-tolyl-methyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide; 66 2-[4-(6-Chloro-benzo[1,3]dioxol-5-ylmethyl)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide; 672-[4-(2-Methoxy-benzyl)-phenyl]-1H-benzoimidazole-5-carboxylic acidamide; 68 2-[4-(2-Methyl-benzyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide; 692-[4-(2-Methyl-benzylsulfamoyl)-phenyl]-1H-benzoimidazole-5- carboxylicacid amide; 702-[4-(3-Methyl-benzylsulfamoyl)-phenyl]-1H-benzoimidazole-5- carboxylicacid amide; 712-[4-(1,3-Dihydro-isoindole-2-sulfonyl)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide; 722-[4-(2,3-Dihydro-indole-1-sulfonyl)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide; 73(±)-2-[4-(1-Phenyl-ethylsulfamoyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide; 74(±)-2-[4-(1,2,3,4-Tetrahydro-naphthalen-1-ylsulfamoyl)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide; 752-{4-[(Thiophen-2-ylmethyl)-sulfamoyl]-phenyl}-1H-benzoimidazole-5-carboxylic acid amide; 762-{4-[(Furan-2-ylmethyl)-sulfamoyl]-phenyl}-1H-benzoimidazole-5-carboxylic acid amide; 772-{4-[(Pyridin-4-ylmethyl)-sulfamoyl]-phenyl}-1H-benzoimidazole-5-carboxylic acid amide; and 782-[4-(S)-Indan-1-ylsulfamoyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide.

Also preferred are compounds selected from the group consisting of:2-{4-[1-(4-Chloro-phenyl)-vinyl]-phenyl}-1H-imidazo[4,5-b]pyridine-5-carboxylicacid amide;2-{4-[(2,4-Dichloro-phenyl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide;2-[4-(3,4-Dihydro-1H-isoquinoline-2-sulfonyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide;2-(4-Thiophen-2-ylmethyl-phenyl)-1H-benzoimidazole-5-carboxylic acidamide; 2-[4-(Furan-3-carbonyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide;2-[4-(Furan-3-yl-hydroxy-methyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide; 2-(4-Furan-3-ylmethyl-phenyl)-1H-benzoimidazole-5-carboxylicacid amide;2-[4-(1-Methyl-1H-imidazole-2-carbonyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide;2-{4-[Hydroxy-(1-methyl-1H-imidazol-2-yl)-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide;2-[4-(1-Methyl-1H-imidazol-2-ylmethyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide;2-[4-(5-Chloro-thiophene-2-carbonyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide;2-{4-[(5-Chloro-thiophen-2-yl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide;2-[4-(5-Chloro-thiophen-2-ylmethyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide;2-[4-(Piperidine-4-carbonyl)-phenyl]-1H-benzoimidazole-5-carboxylic acidamide;2-[4-(Hydroxy-piperidin-4-yl-methyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide;2-(4-Piperidin-4-ylmethyl-phenyl)-1H-benzoimidazole-5-carboxylic acidamide;2-[4-(Tetrahydro-thiopyran-4-carbonyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide;2-{4-[Hydroxy-(tetrahydro-thiopyran-4-yl)-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide;2-[4-(Tetrahydro-thiopyran-4-ylmethyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide;2-[4-(Tetrahydro-pyran-4-ylmethyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide;[[4-(5-Carbamoyl-1H-benzoimidazol-2-yl)-phenyl]-(4-chloro-phenyl)-methoxy]-aceticacid;2-{4-[(2-Amino-ethoxy)-(4-chloro-phenyl)-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide;2-{4-[(4-Chloro-phenyl)-difluoro-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide;2-[4-(Benzo[1,3]dioxol-5-yl-difluoro-methyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide;2-{4-[1-(4-Chloro-phenyl)-1-methyl-ethyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide;2-{4-[(4-Chloro-phenyl)-cyano-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide;2-[4-((S)-1-Hydroxymethyl-1,3-dihydro-isoindole-2-sulfonyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide;2-[4-(R)-1-Hydroxymethyl-1,3-dihydro-isoindole-2-sulfonyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide;2-[4-((1R,2S)-2-Hydroxy-indan-1-ylsulfamoyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide;2-[4-((S)-2-Hydroxy-1-phenyl-ethylsulfamoyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide;2-[4-((R)-2-Hydroxy-1-phenyl-ethylsulfamoyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide; and2-{4-[(Pyridin-2-ylmethyl)-sulfamoyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide.

More preferred are compounds selected from the group consisting of:2-[4-(4-Methyl-benzoyl)-phenyl]-1H-benzoimidazole-5-carboxylic acidamide;2-[4-(Naphthalene-2-carbonyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide;2-[4-(4-Chloro-3-trifluoromethyl-benzoyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide;2-[4-(3-Bromo-4,5-dimethoxy-benzoyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide;2-[4-(3,4-Dichloro-benzoyl)-phenyl]-1H-benzoimidazole-5-carboxylic acidamide;2-[4-(3,4-Dimethyl-benzoyl)-phenyl]-1H-benzoimidazole-5-carboxylic acidamide; 2-[4-(4-Ethyl-benzoyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide; 2-(4-ECyclohexanecarbonyl-phenyl)-1H-benzoimidazole-5-carboxylic acid amide;2-[4-(Hydroxy-phenyl-methyl)-phenyl]-1H-benzoimidazole-5-carboxylic acidamide;2-{4-[(4-Chloro-phenyl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide;2-[4-(Hydroxy-p-tolyl-methyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide;2-{4-[Hydroxy-(4-methoxy-phenyl)-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide;2-[4-(Hydroxy-naphthalen-2-yl-methyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide;2-{4-[(4-Chloro-3-trifluoromethyl-phenyl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide;2-{4-[(3,4-Dichloro-phenyl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide;2-{4-[(3,4-Dimethyl-phenyl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide;2-{4-[(4-Ethyl-phenyl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide;2-[4-(Benzo[1,3]dioxol-5-yl-hydroxy-methyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide;2-[4-(Hydroxy-quinolin-3-yl-methyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide;2-[4-(4-Chloro-benzyl)-phenyl]-1H-benzoimidazole-5-carboxylic acidamide; 2-(4-Naphthalen-2-ylmethyl-phenyl)-1H-benzoimidazole-5-carboxylicacid amide;2-[4-(3,4-Dimethyl-benzyl)-phenyl]-1H-benzoimidazole-5-carboxylic acidamide; 2-[4-(4-Ethyl-benzyl)-phenyl]-1H-benzoimidazole-5-carboxylic acidamide;2-[4-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide;2-{4-[1-(4-Chloro-phenyl)-vinyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide;2-{4-[1-(4-Chloro-phenyl)-ethyl]-phenyl)-1H-benzoimidazole-5-carboxylicacid amide;2-[4-(1,3-Dihydro-isoindole-2-sulfonyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide;2-[4-(2,3-Dihydro-indole-1-sulfonyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide;(±)-2-[4-(1,2,3,4-Tetrahydro-naphthalen-1-ylsulfamoyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide;2-{4-[(Thiophen-2-ylmethyl)-sulfamoyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide; and2-[4-(Indan(S)-1-ylsulfamoyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide.

Most preferred are compounds selected from the group consisting of:2-[4-(Naphthalene-2-carbonyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide;2-[4-(3,4-Dichloro-benzoyl)-phenyl]-1H-benzoimidazole-5-carboxylic acidamide;2-{4-[(4-Chloro-phenyl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide;2-[4-(Hydroxy-naphthalen-2-yl-methyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide;2-{4-[(4-Chloro-3-trifluoromethyl-phenyl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide;2-{4-[(3,4-Dichloro-phenyl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide;2-(4-[(3,4-Dimethyl-phenyl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide;2-[4-(Hydroxy-quinolin-3-yl-methyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide;2-[4-(4-Chloro-benzyl)-phenyl]-1H-benzoimidazole-5-carboxylic acidamide; 2-(4-Naphthalen-2-ylmethyl-phenyl)-1H-benzoimidazole-5-carboxylicacid amide;2-[4-(3,4-Dimethyl-benzyl)-phenyl]-1H-benzoimidazole-5-carboxylic acidamide;2-{4-[1-(4-Chloro-phenyl)-vinyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide;2-{4-[1-(4-Chloro-phenyl)-ethyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide;2-[4-(1,3-Dihydro-isoindole-2-sulfonyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide; and2-[4-(S)-Indan-1-ylsulfamoyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide.

Most preferred are compounds selected from the group consisting of:2-[4-(Hydroxy-phenyl-methyl)-phenyl]-1H-benzoimidazole-5-carboxylic acidamide;2-{4-[(4-Chloro-phenyl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide;2-[4-(Hydroxy-p-tolyl-methyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide;2-{4-[Hydroxy-(4-methoxy-phenyl)-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide;2-[4-(Hydroxy-naphthalen-2-yl-methyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide;2-{4-[(4-Chloro-3-trifluoromethyl-phenyl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide;2-{4-[(3-Bromo-4,5-dimethoxyphenyl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide;2-{4-[(3,4-Dichloro-phenyl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide;2-{4-[(3,4-Dimethyl-phenyl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide;2-{4-[(4-Ethyl-phenyl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide;2-[4-(Benzo[1,3]dioxol-5-yl-hydroxy-methyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide;2-{4-[(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide;2-[4-(Hydroxy-quinolin-3-yl-methyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide;2-[4-(Hydroxy-pyridin-4-yl-methyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide;2-[4-(Cyclohexyl-hydroxy-methyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide;2-{4-[Hydroxy-(tetrahydro-pyran-4-yl)-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide;2-[4-(Hydroxy-thiophen-2-yl-methyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide;2-{4-[(6-Chloro-benzo[1,3]dioxol-5-yl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide;2-{4-[(2-Chloro-phenyl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide;2-{4-[(2,4-Dichloro-phenyl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide;2-{4-[Hydroxy-(2-methoxy-phenyl)-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide;2-[4-(Hydroxy-o-tolyl-methyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide; and2-{4-[(2,4-Dichloro-phenyl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide.

Related Compounds

The invention provides the disclosed compounds and closely related,pharmaceutically acceptable forms of the disclosed compounds, such assalts, esters, amides, acids, hydrates or solvated forms thereof; maskedor protected forms; and, racemic mixtures, or enantiomerically oroptically pure forms. Related compounds also include compounds of theinvention that have been modified to be detectable, e.g., isotopicallylabelled with ¹¹C, or ¹⁸F for use as a molecular probe in positronemission tomography (PET) or single-photon emission computed tomography(SPECT).

The invention also includes disclosed compounds having one or morefunctional groups (e.g., hydroxyl, amino, or carboxyl) masked by aprotecting group. See, e.g., Greene and Wuts, Protective Groups inOrganic Synthesis, 3^(rd) ed., (1999) John Wiley & Sons, NY. Some ofthese masked or protected compounds are pharmaceutically acceptable;others will be useful as intermediates. Synthetic intermediates andprocesses disclosed herein, and minor modifications thereof, are alsowithin the scope of the invention.

C. SYNTHETIC METHODS

The invention provides methods of making the disclosed compoundsaccording to traditional organic synthetic methods as well as matrix orcombinatorial synthetic methods. Schemes 1 through 9 describe suggestedsynthetic routes. Using these Schemes, the guidelines below, and theexamples, a person of skill in the art may develop analogous or similarmethods for a given compound that are within the invention.

One skilled in the art will recognize that synthesis of the compounds ofthe present invention may be effected by purchasing an intermediate orprotected intermediate compounds described in any of the schemesdisclosed herein. One skilled in the art will further recognize thatduring any of the processes for preparation of the compounds in thepresent invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. This maybe achieved by means of conventional protecting groups, such as thosedescribed in “Protective Groups in Organic Synthesis”, John Wiley &Sons, 1991. These protecting groups may be removed at a convenient stageusing methods known from the art.

Examples of the described synthetic routes include Synthetic Examples 1through 78. Compounds analogous to the target compounds of theseexamples can be, and in many cases, have been, made according to similarroutes. The disclosed compounds are useful in basic research and aspharmaceutical agents as described in the next section.

Broadly, compounds of formula I may be made according to Scheme 1.Aldehyde (III) can be condensed with diamine (II) in the presence of anoxidizing agent such as Na₂S₂O₅ to provide benzimidazoles (I). Thisreaction takes place in a solvent, such as DMA or DMF, with theapplication of heat. Better yields might be obtained where the reactionis heated to a temperature of from 80° C. to 100° C. However in the casethat Z is a carbonyl, better yields are obtained at a reactiontemperature of 60° C. Compounds where Z contains an alcohol form a dimerin this reaction, which must be hydrolyzed in the presence of water andan acid at elevated temperatures. Improved yields for compounds where Zis an alcohol may be obtained as described below for Scheme 6.

Schemes 2, 3, 4 and 5 show the formation of various aldehyde (III)subtypes. Referring to Scheme 2, a ketone (IV) may be protected to form,for example, a dioxolane. Lithium halogen exchange of the bromide with asuitable alkyllithium reagent such as n-BuLi, followed by a DMF quenchwill produce aldehyde (IIIa). Other protecting groups amenable tolithium halogen exchange chemistry may also be employed. In this regard,reference is made to “Protective Groups in Organic Synthesis”, JohnWiley & Sons, 1991. Deprotection of the ketone protecting group, in thiscase with a suitable acid such as perchloric acid, affords aldehyde(IIIb). Other functional groups in A or in R_(c) that are sensitive tochemistry utilizing butyl lithium should be protected. For example, acarbonyl group should be protected as the ketal as described for Z.

Referring to Scheme 3, anilines (V) may be halogenated in the paraposition by treatment with a brominating agent such asN-bromosuccinimide. Lithium halogen exchange as described above followedby a DMF quench can be used to produce aldehydes of type (IIIc). Groupsin A or in R_(c) that are sensitive to chemistry utilizing butyl lithiumshould be protected. For example, a carbonyl group should be protectedas the ketal as described for Z. In one alternative to Scheme 3, aphenyl alkyl amine may be cross-coupled with 4-bromobenzaldehyde in thepresence of a palladium catalyst to produce aldehyde (IIIc).

Referring to Scheme 4, an aldehyde/ketone (VI) undergoes a Grignardreaction with an appropriate Grignard reagent (VII) that contains amasked aldehyde to produce bicyclic alcohol (VIII). Where X₁ ishydrogen, alcohol (VII) is oxidized and deprotected to the aldehyde(IIIb). Where there are groups in A or R_(c) that are sensitive tooxidation, mild oxidation conditions should be employed such as TEMPO orPDC or an appropriate protecting group should be employed. Where X₁ isalkyl, alcohol (VII) is exposed to perchloric acid, allowing fordeprotection of the aldehyde in addition to dehydration of the alcoholto form aldehyde (IIId). Hydrogenation of the double bond in compoundsof formula (I) derived from (IIId) can lead to alternative embodimentsof formula (I) in which Z is >CR_(d)R_(d). Where there are groups in Aor R_(c) that are sensitive to oxidation, mild deprotection conditionsshould be employed conc. HCl in THF. Where X₁ is hydrogen, alcohol (VII)is exposed to a protic acid which deprotects to form aldehyde (IIIe).Where there are groups in A or R_(c) that are sensitive to oxidizingconditions non-oxidizing acids should be used for the deprotection suchas HCl.

Referring to Scheme 5, substituted amine (X) is sulfonylated with aformylated benzene sulfonyl chloride derivative (IX) to produce aldehyde(IIIf). In the case that X₁, R_(c) or A contains a primary alcohol thenthis alcohol should be protected with an acid sensitive protectinggroup, such as a silyl-ether. The bicyclic A fused sulfonamides may beproduced in Scheme 5 where the depicted cyclic substituted amine isreplaced with an amine of the formula

where A is fused at the a or b faces, or

where A is fused at the a or b faces.

Referring to Scheme 6, compounds of formula (XIb) can be obtained byreducing compounds of formula (XIa) with NaBH₄, LiBH₄, Na(OAc)₃BH,DIBAL-H or other reducing agent. Compounds of formula (XIb) may befurther reduced with reducing agents, including NaBH₄,triethylsilylhydride, TES—Cl or TMS—Cl to obtain compounds of formula(XIc). Compounds of formula (XIb) may be alkylated to form compounds offormula (XId) by various methods. In the depicted method, the alcohol isconverted to a good leaving group, such as a chloride, using either HClor SOCl₂, and the resulting benzyl chloride may be displaced with avariety of alcohols to produce the corresponding ether (XId). In anothermethod, a base, such as NaH, is used with an alkylating agent, such asMeI, to form a methyl ether. The desired R_(e) may be obtained with,various alkylating agents. Compounds of formula (XIb) may be aminated toform compounds of formula (XIe) by first forming the chloride withchlorinating agents such as SOCl₂ or HCl and subsequently displacing thechloride with the appropriate amine.

Referring to Scheme 7, compounds of formula (XIg) can be obtained bynucleophilic addition of an appropriate Grignard or lithium reagent tocompound (XIa). The resulting tertiary alcohol may then be converted toethers or amines of type (XIh) or (XIj) using the methods described inScheme 6. Compounds of formula (XIg) can also be converted into analogsof formula (IIId) in Scheme 4 by treatment with perchloric acid. Theresulting double bond can be hydrogenated to access alternativeembodiments of formula (I) in which Z is >CR_(d)R_(d).

Referring to Scheme 8, the carboxylic acid of formula (XII) can beconverted to an amide by treatment with 1,1′-carbonyldiimidazole (CDI),or other similar activating agent, followed by a nucleophilic amine toprovide compounds of formula (XIII). Standard peptide couplingconditions, known to one skilled in the art are also applicable.

Compounds of general formula (XIX) can be synthesized using the methodsoutlined in Scheme 9. Treatment of pyridine (XIV) with an ammoniumequivalent such as (NH₄)₂CO₃ provides 2-aminopyridine (XV). Removal ofthe methyl group in (XV) with hydrobromic acid and acetic acid, followedby conversion to the bromide using a nucleophilic bromide source such as(C₄H₉)₄N⁺Br⁻, in the presence of P₂O₅, gives compound (XVI). Treatmentof the bromide with a metallic cyanide such as CuCN then results in theformation of compound (XVII). Reduction of the nitro group of (XVII)using H₂ and Pd or other reducing agent, followed by condensation withan aryl aldehyde of type (III) in the presence of an oxidizing agentsuch as Na₂S₂O₅ provides imidazopyridines of general formula (XVIII).The cyano group of (XVIII) can then be converted to an amide of formula(XIX) by hydrolysis with BF₃ in acetic acid.

D. FORMULATION AND ADMINISTRATION

The present compounds inhibit the checkpoint modulator Cds1 andtherefore are useful as a medicine especially in methods for treatingpatients suffering from disorders or conditions that are modulated orregulated by Cds1, such as cancer.

The invention features a method for treating a subject with cancer, saidmethod comprising administering to the subject a therapeuticallyeffective amount of a pharmaceutical composition comprising a compoundof the invention. The invention also provides a method for inhibitingCds1 activity in a subject, wherein the method comprises administeringto the subject a therapeutically effective amount of a pharmaceuticalcomposition comprising a compound of the invention.

The compounds of the present invention may be formulated into variouspharmaceutical forms for administration purposes. To prepare thesepharmaceutical compositions, an effective amount of a particularcompound, in base or acid addition salt form, as the active ingredientis intimately mixed with a pharmaceutically acceptable carrier.

A carrier may take a wide variety of forms depending on the form ofpreparation desired for administration. These pharmaceuticalcompositions are desirably in unitary dosage form suitable, preferably,for oral administration, intravenous injection or parenteral injection.For example, in preparing the compositions in oral dosage form, any ofthe usual pharmaceutical media may be employed. These include water,glycols, oils, alcohols and the like in the case of oral liquidpreparations such as suspensions, syrups, elixirs and solutions; orsolid carriers such as starches, sugars, kaolin, lubricants, binders,disintegrating agents and the like in the case of powders, pills,capsules and tablets. In view of their ease in administration, tabletsand capsules represent the most advantageous oral dosage unit form, inwhich case solid pharmaceutical carriers are generally, employed. Forparenteral compositions, the carrier will usually comprise sterilewater, at least in large part, though other ingredients, for example, toaid solubility, may be included. Injectable solutions, for example, maybe prepared in which the carrier comprises saline solution, glucosesolution or a mixture of saline and glucose solution. Injectablesuspensions may also be prepared in which case appropriate liquidcarriers, suspending agents and the like may be employed. In thecompositions suitable for percutaneous administration, the carrieroptionally comprises a penetration enhancing agent and/or a suitablewetting agent, optionally combined with suitable additives of any naturein minor proportions, which additives do not cause a significantdeleterious effect to the skin; Such additives may facilitate theadministration to the skin and/or may be helpful for preparing thedesired compositions. These compositions may be administered in variousways, e.g., as a transdermal patch, as a spot-on, as an ointment. Acidaddition salts of the compounds of formula I, due to their increasedwater solubility over the corresponding base form, are more suitable inthe preparation of aqueous compositions.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in dosage unit form for ease ofadministration and uniformity of dosage. Dosage unit form as used in thespecification herein refers to physically discrete units suitable asunitary dosages, each unit containing a predetermined quantity of activeingredient calculated to produce the desired therapeutic effect inassociation with the required pharmaceutical carrier. Examples of suchdosage unit forms are tablets (including scored or coated tablets),capsules, pills, powder packets, wafers, injectable solutions orsuspensions, teaspoonfuls, tablespoonfuls and the like, and segregatedmultiples thereof.

Pharmaceutically acceptable acid addition salts include thetherapeutically active non-toxic acid addition salt forms that thedisclosed compounds are able to form. The latter can conveniently beobtained by treating the base form with an appropriate acid. Appropriateacids comprise, for example, inorganic acids such as hydrohalic acids,e.g. hydrochloric or hydrobromic acid; sulfuric; nitric; phosphoric andthe like acids; or organic acids such as, for example, acetic,propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic,maleic, fumaric, malic, tartaric, citric, methanesulfonic,ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic,p-aminosalicylic, palmoic and the like acids. The term addition saltalso comprises the solvates that the disclosed compounds, as well as thesalts thereof, are able to form. Such solvates are for example hydrates,alcoholates and the like. Conversely the salt form can be converted bytreatment with alkali into the free base form.

“Stereoisomeric forms” defines all the possible isomeric forms that thecompounds of formula (I) may possess. Unless otherwise mentioned orindicated, the chemical designation of compounds denotes the mixture ofall possible stereochemically isomeric forms, said mixtures containingall diastereomers and enantiomers of the basic molecular structure. Morein particular, stereogenic centers may have the (R)- or(S)-configuration; substituents on bivalent cyclic saturated radicalsmay have either the cis- or trans-configuration. The inventionencompasses stereochemically isomeric forms including diastereoisomers,as well as mixtures thereof in any proportion of the disclosedcompounds. The disclosed compounds may also exist in their tautomericforms. Such forms although not explicitly indicated in the above andfollowing formulae are intended to be included within the scope of thepresent invention. For example, the present invention includes

2-[4-(4-Chloro-benzoyl]-1H-benzoimidazole-5-carboxylic acid amide aswell as

2-[4-(4-Chloro-benzoyl]-3H-benzoimidazole-5-carboxylic acid amide.

Those of skill in the treatment of disorders or conditions mediated bythe Cds1 enzyme could easily determine the effective daily amount fromthe test results presented hereinafter and other information. In generalit is contemplated that a therapeutically effective dose would be from0.001 mg/kg to 100 mg/kg body weight, more preferably from 1 mg/kg to 50mg/kg body weight. It may be appropriate to administer thetherapeutically effective dose as two, three, four or more sub-doses atappropriate intervals throughout the day. Said sub-doses may be,formulated as unit dosage forms, for example, containing 1 mg to 2000mg, and in particular 10 to 500 mg of active ingredient per unit dosageform. Examples include 10 mg, 25 mg, 50 mg, 100 mg, 150 mg, 250 mg, and500 mg dosage forms. Compounds of the invention may also be prepared intime-release or subcutaneous or transdermal patch formulations.Disclosed compound may also be formulated as a spray or other topical orinhalable formulations.

The exact dosage and frequency of administration depends on theparticular compound of formula (I) used, the particular condition beingtreated, the severity of the condition being treated, the age, weightand general physical condition of the particular patient as well asother medication the patient may be taking, as is well known to thoseskilled in the art. Furthermore, it is evident that said effective dailyamount may be lowered or increased depending on the response of thetreated patient and/or depending on the evaluation of the physicianprescribing the compounds of the instant invention. The effective dailyamount ranges mentioned herein are therefore only guidelines.

The next section includes detailed information relating to the use ofthe disclosed compounds.

E. EXAMPLES

General Experimental:

NMR spectra were obtained on either a Bruker model DPX400 (400 MHz) orDPX500 (500 MHz) spectrometer. The format of the ¹H NMR data below is:chemical shift in ppm down field of the tetramethylsilane reference(multiplicity, coupling constant J in Hz, integration).

Mass spectra were obtained on an Agilent series 1100 MSD usingelectrospray ionization (ESI) in either positive or negative node asindicated.

HPLC retention times are reported in minutes, using the methods andconditions reported below.

Method A: Instrument: Agilent HP-1100 Solvent: Acetonitrile (0.05%trifluoroacetic acid, TFA)/H₂O (0.05% TFA) Flow rate: 0.75 mL/minGradient: 1 min at 1% H₂O; 7 min linear ramp to 99% H₂O; 4 min at 99%H₂O. Column: ZORBAX Eclipse XDB-C8 (5 um, 4.6 × 150 mm) Temperature: 35°C. Wavelength: Duel detection at 220 and 254 nM. Method B: Instrument:Agilent HP-1100 Solvent: Acetonitrile (0.05% trifluoroacetic acid,TFA)/H₂O (0.05% TFA) Flow rate: 1.5 mL/min Gradient: 1 min at 1% H₂O;3.5 min linear ramp to 99% H₂O; 1.5 min at 99% H₂O Column: XTerra ® RP₁₈(4.6 × 50 mm) Temperature: 35° C. Wavelength: Duel detection at 220 and254 nM. Method C: Instrument: Agilent HP-1100 Solvent: Acetonitrile(0.05% TFA)/H₂O (0.05% TFA) Flow rate: 1.0 mL/min Gradient: 10%Acetonitrile; 5 min linear ramp to 100% Acetonitrile; 5 min at 100%Acetonitrile. Column: Phenomenex Luna ® C18 (5 um, 4.6 × 150 mm)Temperature: 24° C. Wavelength: Detection at 230, 254 and 280 nM.

Example 1

2-[4-(2-Phenyl-[1,3]dioxolan-2-yl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide

A. 2-(4-Bromo-phenyl)-2-phenyl-[1.3]dioxolane. To a solution of(4-bromo-phenyl)-phenyl-methanone (5.0 g, 19.1 mmol) in anhydroustoluene under N₂ was added ethylene glycol (5.32 mL, 95.5 mmol). Thereaction mixture was heated to reflux for 10 h under a Dean-Stark trap.The mixture was cooled to room temperature (RT), washed with 1 N sodiumhydroxide (100 mL) and H₂O (100 mL), and dried (MgSO₄). Solvent wasremoved under reduced pressure, yielding the title compound as a solid(2.89 g, 49%).

B. 4-(2-Phenyl-[1,3]dioxolan-2-yl)-benzaldehyde. To a solution of2-(4-bromo-phenyl)-2-phenyl-[1,3]dioxolane (500 mg, 1.6 mmol) cooled to−78° C. in anhydrous tetrahydrofuran (THF) (100 mL) under N₂ was addedn-butyllithium (1.1 mL of 1.6 M in hexanes, 1.7 mmol) dropwise. Thereaction mixture was stirred at −78° C. for 30 min, thendimethylformamide (DMF) (0.135 mL, 1.7 mmol) was added dropwise, and themixture was allowed to warm to RT. The mixture was poured into saturatedaqueous NH₄Cl, and the resulting mixture was extracted with diethylether (Et₂O) (2×100 mL). The combined extracts were washed with brine(100 mL) and dried (Na₂SO₄). The solvent was removed under reducedpressure. The title compound was obtained as an oil (350 mg; 84%). ¹HNMR (400 MHz, CDCl₃): δ 9.99 (s, 1H), 7.84 (d, J=8.5 Hz, 2H), 7.71 (d,J=8.2 Hz, 2H), 7.52-7.49 (dd, J=8.4, 1.5 Hz, 2H), 7.36-0.29 (m, 4H),4.12-4.04 (m, 4H).

C.2-[4-(2-Phenyl-[1,3]dioxolan-2-yl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide. To a solution of 3,4-diamino-benzamide (100 mg, 0.6 mmol) inanhydrous DMF was added 4-(2-phenyl-[1,3]dioxolan-2-yl)-benzaldehyde(168 mg, 0.6 mmol) and sodium metabisulfite (164 mg, 0.86 mmol). Themixture was heated to 90° C. under N₂ for 16 h. The reaction mixture wascooled and added dropwise to ice/H₂O. The resulting solids were filteredand washed with H₂O (59 mL) then hexanes (2×50 mL). Purification bychromatography; (silica gel, 1% 1 methanol saturated with ammonia/9%methanol/CH₂Cl₂) afforded 160 mg (63%) of the title compound. TLC(silica, 1% methanol-saturated with ammonia/9% methanol/CH₂Cl₂):R_(f)=0.3. HPLC (Method A): R_(t)=7.02. MS (ESI+): mass calculated forC₂₃H₁₉N₃O₃, 385.1; m/z found, 386.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ8.13 (br s, 1H), 8.04 (d, J=8.4 Hz, 2H), 7.77 (d, J=8.5 Hz, 1H), 7.64(d, J=8.4 Hz, 2H), 7.58 (br s, 1H), 7.49-7.47 (dd, J=8.4. 1.5 Hz, 2H),7.32-7.23 (m, 3H), 4.03 (s, 4H).

Example 2

2-{4-[2-(4-Chloro-phenyl)-[1,3]dioxolan-2-yl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide

A. 2-(4-Bromo-phenyl)-2-(4′-chloro-Phenyl)-[1,3]dioxolane. This compoundwas prepared as described in Example 1 substituting(4-bromo-phenyl)-(4-chloro-phenyl)-methanone (750 mg, 2.5 mmol) for(4-bromo-phenyl)-phenyl-methanone in Step A. The title compound wasrecrystallized from ethanol to afford 680 mg (85%) of white plates. ¹HNMR (400 MHz, CDCl₃): δ 7.45 (d, J=8.7 Hz, 2H), 7.41 (d, J=8.7 Hz, 2H),7.35 (d, J=8.7 Hz, 2H), 7.29 (d, J=8.7 Hz, 2H), 4.04 (m, 4H).

B. 4-[2-(4-Chloro-Phenyl)-[1,3]dioxolan-2-yl]-benzaldehyde. Thiscompound was prepared as described in Example 1 substituting2-(4-bromo-phenyl)-2-(4-chloro-phenyl)-[1,3]dioxolane (300 mg, 0.8 mmol)for 2-(4-bromo-phenyl)-2-phenyl-[1,3]dioxolane in Step B. Purificationby chromatography (silica gel, CH₂Cl₂) afforded 100 mg (39%) of thetitle compound. ¹H NMR (400 MHz, CDCl₃): δ 10.00 (s, 1H), 7.85 (d, J=8.4Hz, 2H), 7.67 (d, J=8.3 Hz, 2H), 7.45 (d, J=8.6 Hz, 2H), 7.30 (d, J=8.6Hz, 2H), 4.07 (m, 4H).

C.2-{4-[2-(4-Chloro-6-phenyl)-[1,3]dioxolan-2-yl]-phenyl}-1H-benzoimidazole-5-carboxylicacid. This compound was prepared as described in Example 1 Step C from4-[2-(4-chloro-phenyl)-[1,3]dioxolan-2-yl]-benzaldehyde (100 mg, 0.34mmol) and 3,4-diamino-benzoic acid (53 mg, 0.34 mmol). The titlecompound was obtained as a tan solid 135 mg (92%). MS (ESI): masscalculated for C₂₃H₁₇ClN₂O₄, 420.1; m/z found, 421.1 [M+H]⁺, 419.1[M−H]⁻. HPLC (Method B): R_(t)=2.43.

D.2-[4-(2-Phenyl-[1,3]dioxolan-2-yl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide. To a solution of2-{4-[2-(4-chloro-phenyl)-[1,3]dioxolan-2-yl]-phenyl}-1H-benzoimidazole-5-carboxylicacid (135 mg, 0.32 mmol) in anhydrous DMF was added carbonyldiimidazole(118 mg, 0.73 mmol). The reaction mixture was stirred under N₂ for 30min and then cooled to 0° C., and ammonium bicarbonate (140 mg, 1.4mmol) was added. The resulting mixture was allowed to warm to RT and wasstirred for 16 h. The mixture was added dropwise to saturated aqueousNH₄Cl. The resulting precipitate was collected by filtration and washedwith H₂O (100 mL) then hexanes (100 mL). The product was dried undervacuum overnight to give the title compound (1.02 mg, 76%). TLC (silica,1% methanol saturated with ammonia/9% methanol/CH₂Cl₂): R_(f)=0.33. HPLC(Method A): R_(t)=7.42. MS (ESI+): mass calculated for C₂₃H₁₈ClN₃O₃,419.1; m/z found, 420.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.09 (s, 1H),8.00 (d, J=8.4 Hz, 2H), 7.75-7.72 (dd, J=8.5, 1.5 Hz, 1H), 7.59 (d,J=8.4 Hz, 2H), 7.56 (br d, J=8.7 Hz, 1H), 7.43 (d, J=8.5 Hz, 2H), 7.27(d, J=8.6 Hz, 2H), 3.99 (s, 4H).

Example 3

2-(4-Benzoyl-phenyl)-1H-benzoimidazole-5-carboxylic acid amide

A. 4-Benzoyl-benzaldehyde. To a cooled (ice/acetone) solution of4-(2-phenyl-[1,3]dioxolan-2-yl)-benzaldehyde (145 mg, 0.57 mmol) inCH₂Cl₂ was added dropwise perchloric acid (70%, 0.38 mL). The reactionmixture was stirred at RT for 2 h, and then was poured into saturatedaqueous NaHCO₃ (75 mL). The aqueous layer was extracted with CH₂Cl₂. Thecombined organic layers were washed with H₂O (2×50 mL) and dried(Na₂SO₄). The solvent was removed under reduced pressure to provide 100mg (83%) of the title compound. ¹H NMR (400 MHz, CDCl₃): δ 10.14 (s,1H), 8.01 (d, J=8.4 Hz, 2H), 7.93 (d, J=8.2 Hz, 2H), 7.83-7.80 (dd,J=8.4, 1.3 Hz, 2H), 7.63 (d, J=7.4 Hz, 1H), 7.52 (t, J=7.6 Hz, 2H).

B. 2-(4-Benzoyl-phenyl)-1H-benzoimidazole-5-carboxylic acid. Thiscompound was prepared as described in Example 1 using4-benzoyl-benzaldehyde (100 mg, 0.47 mmol) and 3,4-diamino-benzoic acid(72 mg, 0.47 mmol) in Step C. The title compound was obtained as a tansolid (135 mg, 85%). MS (ESI): mass calculated for C₂₁H₁₄N₂O₃, 342.1;m/z found, 342.9 [M+H]⁺. HPLC (Method A): R_(t)=7.17.

C. 2-(4-Benzoyl-phenyl)-1H-benzoimidazole-5-carboxylic acid amide. Thiscompound was prepared as described in Example 2 using2-(4-benzoyl-phenyl)-1H-benzoimidazole-5-carboxylic acid (138 mg. 0.4mmol) in Step D. The title compound was obtained as a tan solid (54 mg,39%). TLC (silica, 1% methanol saturated with ammonia/9%methanol/CH₂Cl₂): R_(f)=0.31. HPLC (Method A): R_(t)=6.75. MS (ESI+):mass calculated for C₂₁H₁₅N₃O₂, 341.1; m/z found, 342.1 [M+H]⁺. ¹H NMR(400 MHz, CD₃OD): δ 8.19 (d, J=8.2 Hz, 2H), 8.16 (br s, 1H), 7.87 (d,J=8.3 Hz, 2H), 7.80-7.78 (dd, J=8.5, 1.6 Hz, 1H), 7.76 (d, J=8.4 Hz,2H), 7.62-7.60 (m, 2H), 7.49 (t, J=7.5 Hz, 2H), 7.00 (s, 1H).

Example 4

2-[4-(4-Chloro-benzoyl)-phenyl]-1H-benzoimidazole-5-carboxylic acidamide

A. (4-Chloro-phenyl)-(4-[1,3]dioxolan-2-yl-phenyl)-methanol. To asolution of 4-chloro-benzaldehyde (1.98 g, 14.0 mmol) in anhydrous THF,cooled to −78° C., was added, 4-(1,3-dioxolan-2-yl)phenylmagnesiumbromide (60 mL, 0.25 M in THF) dropwise. The reaction mixture wasstirred 1 h at −78° C. then quenched with saturated aqueous NH₄Cl (50mL). The resulting mixture was extracted with Et₂O (2×100 mL). Thecombined extracts were-washed with H₂O (100 mL) then brine (100 mL), anddried (MgSO₄). Solvent was removed under reduced pressure, and theresidue was purified by chromatography (silica gel, 50% ethylacetate/hexanes) to afford the title compound (3.25 g, 79%). TLC(silica, 50% ethyl acetate/hexanes) R_(f)=04. ¹H NMR (500 MHz, CDCl₃): δ7.45 (d, J=8.2 Hz, 2H), 7.36° (d, J=8.1 Hz, 2H), 7.29 (s, 4H), 5.82 (d,J=3.3 Hz, 1H), 4.14-4.08 (m, 2H), 4.06-4.01 (m, 2H).

B. (4-Chloro-phenyl)-(4-[1,3]dioxolan-2-yl-Phenyl)-methanone.(4-Chloro-phenyl)-(4-[1,3]dioxolan-2-yl-phenyl)-methanol (250 mg, 0.85mmol) was dissolved in ethyl acetate (1.5 mL) and treated with asolution of sodium bromide (88 mg, 0.85 mmol) in saturated aqueousNaHCO₃ (2.3 mL). The reaction mixture was cooled to 0° C. and stirredfor 30 min. Free radical 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO)(1.3 mg, 0.008 mmol) and then aqueous sodium hypochlorite solution (1.25mL, 0.67 M) were added, and the resulting mixture was stirred for 2 h.Ethyl acetate (100 mL) and brine (100 mL) were added, and the mixturewas stirred 5 min. The organic layer was washed with brine (2×75 mL) andthen dried (Na₂SO₄). Solvent was removed under reduced pressure yieldingthe title compound as an off-white solid (247 mg, 99%). TLC (silica, 50%ethyl acetate/hexanes): R_(f)=0.5. HPLC (Method A): R_(t)=9.99. MS(ESI+): mass calculated for C₁₆H₁₃ClO₃, 288.0; m/z found, 289.0 [M+H]⁺.¹H NMR (500 MHz, CDCl₃): δ 7.78 (d, J=8.3 Hz, 2H), 7.75 (d, J=8.6 Hz,2H), 7.61 (d, J=8.1 Hz, 2H), 7.46 (d, J=8.6 Hz, 1H), 5.89 (s, 1H),4.16-4.12 (m, 2H), 4.11-4.06 (m, 2H).

C. 4-(4-Chloro-benzoyl)-benzaldehyde. This compound was prepared asdescribed in Example 3 using(4-chloro-phenyl)-(4-[1,3]dioxolan-2-yl-phenyl)-methanone in Step A. TLC(silica, 50% ethyl acetate/hexanes): R_(f)=0.6. HPLC (Method A):R_(t)=9.93. MS (ESI+): mass calculated for C₁₄H₉ClO₂, 244.0; m/z found,245.0 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): δ 10.13 (s, 1H), 8.01 (d, J=8.4Hz, 2H), 7.90 (d, J=8.2 Hz, 2H), 7.76 (d, J=8.6 Hz, 2H), 7.49 (d, J=8.6Hz, 2H).

D. 2-[4-(4-Chloro-benzoyl)-phenyl]-1H-benzoimidazole-5-carboxylic acidamide. To a solution of 3,4-diamino-benzamide (92 mg, 0.6 mmol) inanhydrous-dimethyacetamide (DMA) (10 mL) was added4-(4-chloro-benzoyl)-benzaldehyde (150 mg, 0.6 mmol) and sodiummetabisulfite (151 mg, 0.79 mmol). The mixture was heated to 60° C.under N₂ for 16 h. The reaction mixture was cooled and added dropwise toice/H₂O. The resulting solids were filtered and washed with H₂O (50 mL)then hexanes (2×50 mL). Purification by chromatography (silica gel, 1%methanol saturated with ammonia/9% methanol/CH₂Cl₂) afforded-71 mg (31%)of the title compound. TLC (silica, 1% methanol saturated withammonia/9% methanol/CH₂Cl₂): R_(f)=0.3. HPLC (Method A): R_(t)=7.53. MS(ESI+): mass calculated for C₂₁H₁₄ClN₃O₂, 375.1; m/z found, 376.0,[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): δ 13.35 (br s, 1H), 8.38 (d, J=8.3Hz, 2H), 8.01 (br s 1H), 7.94 (d, J=8.3 Hz, 2H), 7.82 (d, J=8.4 Hz, 3H),7.67 (d, J=8.4 Hz, 3H), 7.30 (br s, 1H).

Example 5

2-[4-(4-Methyl-benzoyl)-phenyl]-1H-benzoimidazole-5-carboxylic acidamide

The title compound was prepared as described in Example 4 substituting4-methyl-benzaldehyde for 4-chloro-benzaldehyde in Step A. TLC (silica,1% methanol saturated with ammonia/9% methanol/CH₂Cl₂): R_(f)=0.29. HPLC(Method A): R_(t)=7.36. MS (ESI+): mass calculated for C₂₂H₁₇N₃O₂,355.1; m/z found, 356.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): δ 8.26 (d,J=8.5 Hz, 2H), 8.25 (br s, 1H), 7.93 (d, J=8.5 Hz, 2H), 7.85 (d, J=8.4Hz, 1H), 7.74 (d, J=8.2 Hz, 2H), 7.69 (br s, 1H), 7.38 (d, J=7.8 Hz,2H), 2.46 (s, 3H).

Example 6

2-[4-(4-Methoxy-benzoyl)-phenyl]-1H-benzoimidazole-5-carboxylic acidamide

The title compound was prepared as described in Example 4 substituting4-methoxy-benzaldehyde for 4-chloro-benzaldehyde in Step A. TLC (silica,1% methanol saturated with ammonia/9% methanol/CH₂Cl₂): R_(f)=0.27. HPLC(Method A): R_(t)=7.09. MS (ESI+): mass calculated for C₂₂H₁₇N₃O₃,371.1; m/z found, 372.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): δ 8.25 (d,J=8.4 Hz, 3H), 7.89 (d, J=8.4 Hz, 2H), 7.84 (d, J=8.9 Hz, 3H), 7.68 (brs, 1H), 7.07 (d, J=8.9 Hz, 2H), 3.90 (s, 3H).

Example 7

2-[4-(Naphthalene-2-carbonyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide

The title compound was prepared as described in Example 4 substitutingnaphthalene-2-carbaldehyde for 4-chloro-benzaldehyde in Step A. TLC(silica, 1% methanol saturated with ammonia/9% methanol/CH₂Cl₂):R_(f)=0.25. HPLC (Method A): R_(t)=7.74. MS (ESI+): mass calculated forC₂₅H₁₇N₃O₂, 391.1; m/z found, 392.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): δ8.30 (s, 1H), 8.27 (d, J=8.4 Hz, 2H), 8.23 (br s, 1H), 8.02-7.95 (m,5H), 7.92-7.90 (dd, J=8.5, 1.6 Hz, 1H), 7.85 (br d, J=7.8 Hz, 1H), 7.68(br s, 1H), 7.66-7.62 (td, J=7.5, 1.1 Hz, 1H), 7.59-7.56 (td, J=7.5, 1.1Hz, 1H).

Example 8

2-[4-(4-Chloro-3-trifluoromethyl-benzoyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide

The title compound was prepared as described in Example 4 substituting4-chloro-3-trifluoromethyl-benzaldehyde for 4-chloro-benzaldehyde inStep A. TLC (silica, 1% methanol saturated with ammonia/9%methanol/CH₂Cl₂): R_(f)=0.25. HPLC (Method A): R_(t)=8.20. MS (ESI−):mass-calculated for C₂₂H₁₃ClF₃N₃O₂, 443.1; m/z found, 442.5 [M−H]⁻. ¹HNMR (500 MHz, CD₃OD): δ 8.30 (d, J=8.5 Hz, 2H), 8.23 (br s, 1H), 8.20(d, J=1.9 Hz, 1H), 8.05-8.03 (dd, J=8.2, 2.0 Hz, 1H), 7.99 (d, J=8.6 Hz,2H), 7.86 (br d, J=8.3 Hz, 1H), 7.83 (d, J=8.3 Hz, 1H), 7.69 (br s, 1H).

Example 9

2-[4-(3-Bromo-4,5-dimethoxy-benzoyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide

A. (3,4-Dimethoxy-Phenyl)-(4-[1,3]dioxolan-2-yl-phenyl)-methanol. Thiscompound was prepared as described in Example 4 substituting3,4-dimethoxy-benzaldehyde for 4-chloro-benzaldehyde in Step A. HPLC(Method A): R_(t)=8.01. ¹H NMR (500 MHz, CDCl₃): δ 7.46 (d, J=8.2 Hz,2H), 7.40 (d, J=8.1 Hz, 2H), 6.90 (d, J=1.9 Hz, 1H), 6.87-6.85 (dd,J=8.3, 1.9 Hz, 1H), 6.81 (d, J=8.2 Hz, 1H), 5.81 (d, J=3.5 Hz, 1H), 5.80(s, 1H), 4.13-4.09 (m, 2H), 4.06-4.01 (m, 2H), 3.86 (s, 3H), 3.84 (s,3H), 2.17-2.04 (m, 1H).

B.(3-Bromo-4,5-dimethoxy-phenyl)-(4-[1.3]dioxolan-2-yl-phenyl)-methanone.To a solution of(3,4-dimethoxy-phenyl)-(4-[1,3]dioxolan-2-yl-phenyl)-methanol (600 mg,1.8 mmol) in ethyl acetate (5.0 mL) was added a solution of sodiumbromide (253 mg, 2.4 mmol) in saturated aqueous NaHCO₃ (5.25 mL). Thereaction mixture was cooled to 0° C. TEMPO (3.0 mg, 0.018 mmol) and thenaqueous sodium hypochlorite solution (2.9 mL, 0.67 M) were added, andthe resulting mixture was stirred for 2 h. Ethyl acetate (100 mL) andbrine (100 mL) were added, and the mixture was stirred 5 min. Theorganic layer was washed with brine (2×75 mL) and then dried (Na₂SO₄).The solvent was removed under reduced pressure. Purification bychromatography (silica gel, 50% ethyl acetate/hexanes) afforded 312 mg(42%) of the title compound. MS (ESI+): mass calculated for C₁₈H₁₇BrO₅,392.0; m/z found, 394.0 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): δ 7.83 (d,J=8.3 Hz, 2H), 7.58 (d, J=8.3 Hz, 2H), 7.08 (s, 1H), 6.87 (s, 1H), 5.86(s, 1H), 4.16-4.10 (m, 2H), 4.09-4.03 (m, 2H), 3.94 (s, 3H), 3.84 (s,3H).

C. 4-(3-Bromo-4,5-dimethoxy-benzoyl)-benzaldehyde. This compound wasprepared as described in Example 3 substituting(3-bromo-4,5-dimethoxy-phenyl)-(4-[1,3]dioxolan-2-yl-phenyl)-methanone(300 mg, 0.7 mmol) for 4-(2-phenyl-[1,3]dioxolan-2-yl)-benzaldehyde inStep A. Purification by chromatography (silica gel, 50% ethylacetate/hexanes) afforded 210 mg (79%) of the title compound. TLC(silica, 50% ethyl acetate/hexanes): R_(f)=0.47. ¹H NMR (500 MHz,CDCl₃): δ 10.12 (s, 1H), 8.01-7.91 (m, 4H), 7.09 (s, 1H), 6.94 (s, 1H),3.95 (s, 3H), 3.87 (s, 3H).

D.2-[4-(3-Bromo-4,5-dimethoxy-benzoyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide. This compound was prepared as described in Example 4substituting 4-(3-bromo-4,5-dimethoxy-benzoyl)-benzaldehyde (210 mg, 0.5mmol) for 4-(4-chloro-benzoyl)-benzaldehyde in Step D. Purification bychromatography (silica gel, 1% methanol saturated with ammonia/9%methanol/CH₂Cl₂) afforded 236 mg (53%) of the title compound. TLC(silica, 1% methanol saturated with ammonia/9% methanol/CH₂Cl₂):R_(f)=0.45. HPLC (Method A): R_(t)=7.45. MS (ESI+): mass calculated forC₂₃H₁₈BrN₃O₄, 479.0; m/z found, 480.0/482.0 [M+H]⁺. ¹H NMR (500 MHz,CD₃OD): δ 8.21 (br s, 1H), 8.20 (d, J=8.5 Hz, 2H), 7.91 (d, J=8.5 Hz,2H), 7.84-7.82 (dd, J=8.5-1.7 Hz, 1H), 7.65 (d, J=8.3 Hz, 1H), 7.21 (s,1H), 7.04 (s, 1H), 3.90 (s, 3H), 3.82 (s, 3H).

Example 10

1,2-[4-(3,4-Dichloro-benzoyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide

The title compound was prepared as described in Example 4 substituting3,4-dichloro-benzaldehyde for 4-chloro-benzaldehyde in Step A. TLC(silica, 1% methanol saturated with ammonia/9% methanol/CH₂Cl₂):R_(f)=0.32. MS (ESI+): mass calculated for C₂₁H₁₃Cl₂N₃O₂, 409.0°; m/zfound, 409.9/411.9[M+H]⁺. ¹H NMR (500 MHz, CD₃OD): δ8.20 (d, J=8.5 Hz,2H), 8.19 (br s, 1H), 7.89 (s, 1H), 7.88 (d, J=8.7 Hz, 2H), 7.82-7.80(dd, J=8.5, 1.6 Hz, 1H), 7.68-7.62 (m, 3H).

Example 11

2-[4-(3,4-Dimethyl-benzoyl)-phenyl]-1H-benzoimidazole-5-carboxylic acidamide

The title compound was prepared as described in Example 4 substituting3,4-dimethyl-benzaldehyde for 4-chloro-benzaldehyde in Step A. TLC(silica, 1% methanol saturated with ammonia/9% methanol/CH₂Cl₂):R_(f)=0.28. HPLC (Method A): R_(t)=7.53. MS (ESI+): mass calculated forC₂₃H₁₉N₃O₂, 369.1; m/z found, 370.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): δ8.25 (d, J=8.4 Hz, 2H), 8.22 (s, 1H), 7.91 (d, J=8.3 Hz, 2H), 7.86-7.84(dd, J=8.5, 1.6 Hz, 1H), 7.68 (br d, J=8.4 Hz, 1H), 7.60 (s, 1H), 7.53(br d, J=7.7 Hz, 1H), 7.30 (d, J=7.7 Hz, 1H), 2.37 (s, 3H), 2.34 (s,3H).

Example 12

2-[4-(4-Ethyl-benzoyl)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide

The title compound was prepared as described in Example 4 substituting4-ethyl-benzaldehyde for 4-chloro-benzaldehyde in Step A. TLC (silica,1% methanol saturated with ammonia/9% methanol/CH₂Cl₂): R_(f)=0.29. HPLC(Method A): R_(t)=7.67. MS (ESI+): mass calculated for C₂₃H₁₉N₃O₂,369.1; m/z found, 370.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃ D): δ 8.24 (d,J=8.5 Hz, 2H), 8.22 (s, 1H), 7.91 (d, J=8.6 Hz, 2H), 7.85-7.83 (dd,J=8.5, 1.6 Hz, 1H), 7.74 (d, J=8.2 Hz, 2H), 7.67 (d, J=8.4 Hz, 1H), 7.39(d, J=8.1 Hz, 2H), 2.77-2.73 (q, J=7.6 Hz, 2H), 1.28 (t, J=7.6 Hz, 3H).

Example 13

2-[4-(Benzo[1,3]dioxole-5-carbonyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide

The title compound was prepared as described in Example 4 substitutingbenzo[1,3]dioxole-5-carbaldehyde for 4-chloro-benzaldehyde in Step A.TLC (silica, 1% methanol saturated with ammonia/9% methanol/CH₂Cl₂):R_(f)=0.28. HPLC (Method A): R_(t)=7.08. MS (ESI+): mass calculated forC₂₂H₁₅N₃O₄, 385.1; m/z found, 386.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): δ8.26 (d, J=8.4 Hz, 2H), 8.23 (br s, 1H), 7.90 (d, J=8.4 Hz, 2H),7.86-7.84 (dd, J=8.5, 1.6 Hz, 1H), 7.69 (d, J=8.3 Hz, 1H), 7.42-7.40(dd, J=8.1, 1.7 Hz, 1H), 7.35 (d, J=1.6 Hz, 1H), 6.96 (d, J=8.1 Hz, 1H),6.1 (s, 2H).

Example 14

2-[4-(2,3-dihydro-benzo[1,4]dioxine-6-carbonyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide

The title compound was prepared as described in Example 4 substituting2,3-dihydro-benzo[1,4]dioxine-6-carbaldehyde for 4-chloro-benzaldehydein Step A. TLC (silica, 1% methanol saturated with ammonia/9%methanol/CH₂Cl₂): R_(f)=0.30. HPLC (Method A): R_(t)=7.29. MS (ESI+):mass calculated for C₂₃H₁₇N₃O₄, 399.1; m/z found, 400.1 [M+H]⁺. ¹H NMR(500 MHz, CD₃OD): δ 8.23 (d, J=8.5 Hz, 2H), 8.21 (s, 1H), 7.87 (d, J=8.5Hz, 2H), 7.85-7.83 (dd, J=8.5, 1.6 Hz, 1H), 7.67 (br d, J=8.4 Hz, 1H),7.35-7.33 (m, 2H), 6.96 (d, J=8.9 Hz, 1H), 4.35-4.33 (m, 2H), 4.30-4.28(m, 2H).

Example 15

2-[4-(Quinoline-3-carbonyl)-phenyl]-1H-benzoimidazole-5-carboxylic acidamide

The title compound was prepared as described in Example 4 substitutingquinoline-3-carbaldehyde for 4-chloro-benzaldehyde in Step A. TLC(silica, 1% methanol saturated with ammonia/9% methanol/CH₂Cl₂):R_(f)=0.20. HPLC (Method A): R_(t)=6.96. MS (ESI+): mass calculated forC₂₄H₁₆N₄O₂, 392.1; m/z found, 393.1 [M+H]⁺. ¹H NMR (500 MHz,CD₃OD/DMSO-d₆): δ 9.28 (d, J=2.2 Hz, 1H), 8.80 (d, J=2.1 Hz, 1H), 8.41(d, J=8.1 Hz, 2H), 8.24 (br s, 1H), 8.17-8.16 (dd, J=6.1, 0.8 Hz, 2H),8.09 (d, J=8.3 Hz, 2H), 7.97-7.94 (m, 1H), 7.87-7.85 (dd, J=8.4, 1.2 Hz,1H), 7.74 (t, J=7.1 Hz, 1H), 7.71 (br d, J=8.3 Hz, 1H).

Example 16

2-[4-(Pyridine-4-carbonyl)-phenyl]-1H-benzoimidazole-5-carboxylic acidamide

The title compound was prepared as described in Example 4 substitutingpyridine-4-carbaldehyde for 4-chloro-benzaldehyde in Step A. TLC(silica, 1% methanol saturated with ammonia/9% methanol/CH₂Cl₂):R_(f)=0.25. HPLC (Method A): R_(t)=6.22. MS (ESI+): mass calculated forC₂₀H₁₄N₄O₂, 342.1; m/z found, 343.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): δ8.80 (d, J=6.0 Hz, 2H), 8.29 (d, J=8.4 Hz, 2H), 8.22 (br s, 1H), 8.01(d, J=8.4 Hz, 2H), 7.86 (br d, J=8.3 Hz, 1H), 7.74 (d, J=6.0 Hz, 2H),7.68 (br s, 1H).

Example 17

2-(4-Cyclohexanecarbonyl-phenyl)-1H-benzoimidazole-5-carboxylic acidamide

The title compound was prepared as described in Example 4 substitutingcyclohexanecarbaldehyde for 4-chloro-benzaldehyde in Step A. TLC(silica, 1% methanol saturated with ammonia/9% methanol/CH₂Cl₂):R_(f)=0.29. HPLC (Method A): R_(t)=7.50. MS (ESI+): mass calculated forC₂₁H₂₁N₃O₂, 347.2, m/z found, 347.7 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): δ8.13 (d, J=8.5 Hz, 2H), 8.12 (br s, 1H), 8.03 (d, J=8.6 Hz, 2H),7.75-7.73 (dd, J=8.5, 1.2 Hz, 1H), 7.58 (br d, J=7.3 Hz, 1H), 3.36-3.31(m, 1H), 1.83-1.77 (m, 2H), 1.76-1.73 (m, 2H), 1.68-1.64 (m, 1H),1.45-1.32 (m, 4H), 1.23-1.18 (m, 1H).

Example 18

2-[4-(4-Chloro-benzoyl)-phenyl]-1H-benzoimidazole-5-sulfonic acid amide

The title compound was prepared as described in Example 1 substituting3,4-diamino-benzenesulfonamide for 3,4-diamino-benzamide and4-(4-chloro-benzoyl)-benzaldehyde for4-(2-phenyl-[1,3]dioxolan-2-yl)-benzaldehyde in Step C (reaction mixturewas heated to 60° C.). TLC (silica, 1% methanol saturated withammonia/9% methanol/CH₂Cl₂): R_(f)=0.32. HPLC (Method A): R_(t)=8.03. MS(ESI+): mass calculated for C₂₀H₁₄ClN₃O₃S, 411.0; m/z found, 412.0[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): δ 13.48 (br s, 1H), 8.31 (d, J=8.3Hz, 2H), 8.16 (br s, 1H), 7.88 (d, J=8.3 Hz, 2H), 7.76 (br s, 1H), 7.74(d, J=8.5 Hz, 2H), 7.73 (br s, 1H), 7.60 (d, J=8.5 Hz, 2H), 7.25 (br s,2H).

Example 19

2-[4-(Hydroxy-phenyl-methyl)-phenyl]-1H-benzoimidazole-5-carboxylic acidamide

To a solution of 2-(4-benzoyl-phenyl)-1H-benzoimidazole-5-carboxylicacid amide (Example 3, 18 mg, 0.05 mmol) in anhydrous methanol (2.0 mL)was added sodium borohydride (2.0 mg, 0.05 mmol) in one portion. Thereaction mixture was stirred under N₂ for 1 h. The solvent was removedunder reduced pressure, and the residue was re-dissolved in 1:1 ethylacetate/H₂O (40 mL). The solution was washed with H₂O (20 mL) then brine(20 mL) and dried (Na₂SO₄). Solvent was removed under reduced pressure,and purification by chromatography (silica gel, 1% methanol saturatedwith ammonia/9% methanol/CH₂Cl₂) afforded 15 mg (83%) of the titlecompound. TLC (silica, 1% methanol saturated with ammonia/9%methanol/CH₂Cl₂): R_(f)=0.13. HPLC (Method A): R_(t)=6.36. MS (ESI+):mass calculated for C₂₁H₁₇N₃O₂, 343.1; m/z found, 344.1 [M+H]⁺. ¹H NMR(400 MHz, CD₃OD): δ 8.17 (br s, 1H), 8.07 (d, J=8.4 Hz, 2H), 7.82-7.80(dd, J=8.4, 1.4 Hz, 1H), 7.63 (br d, J=6.7 Hz, 1H), 7.58 (d, J=8.2 Hz,2H), 7.42-7.40 (dd, J=8.5, 1.4 Hz, 2H), 7.32 (t, =J=7.5 Hz, 2H),7.26-7.22 (m, 1H), 5.85 (s, 1H).

Example 20

2-{4-[(4-Chloro-phenyl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide

The title compound was prepared as described in Example 19 from2-[4-(4-chloro-benzoyl)-phenyl]-1H-benzoimidazole-5-carboxylic acidamide (Example 4, 22 mg, 0.06 mmol). Purification by chromatography(silica gel, 1% methanol saturated with ammonia/9% methanol/CH₂Cl₂)afforded 13 mg (60%) of the title compound. TLC (silica, 1% methanolsaturated with ammonia/9% methanol/CH₂Cl₂): R_(f)=0.14. HPLC (Method A):R_(t)=7.02. MS (ESI+): mass calculated for C₂₁H₁₆ClN₃O₂, 377.1; m/zfound, 378.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): δ 8.17 (br s, 1H), 8.08(d, J=8.4 Hz, 2H), 7.81 (br d, J=7.5 Hz, 1H), 7.64 (br s, 1H), 7.57 (d,J=8.2 Hz, 2H), 7.40 (d, J=8.4 Hz, 2H), 7.33 (d, J=8.6 Hz, 2H), 5.85 (s,1H).

Example 21

2-[4-(Hydroxy-p-tolyl-methyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide

The title compound was prepared as described in Example 19 from2-[4-(4-methyl-benzoyl)-phenyl]-1H-benzoimidazole-5-carboxylic acidamide (Example 5, 60 mg, 6.16 mmol). Purification by chromatography(silica gel, 1% methanol saturated with ammonia/9% methanol/CH₂Cl₂)afforded 55 mg (91%) of the title compound. TLC (silica, 1% methanolsaturated with ammonia/9% methanol/CH₂Cl₂): R_(f)=0.2. HPLC (Method A):R_(t)=6.89. MS (ESI+): mass calculated for C₂₂H₁₉N₃O₂, 357.1; m/z found,358.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): δ 8.21-8.11 (br m, 1H), 8.06 (d,J=8.3 Hz, 2H), 7.80 (br s, 1H), 7.67 (br s, 1H), 7.56 (d, J=8.2 Hz, 2H),7.28 (d, J=8.0 Hz, 2H), 7.15 (d, J=7.9 Hz, 2H), 5.82 (s, 1H), 2.30 (s,3H).

Example 22

2-{4-[Hydroxy-(4-methoxy-phenyl)-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide

The title compound was prepared as described in Example 19 from2-[4-(4-methoxy-benzoyl)-phenyl]-1H-benzoimidazole-5-carboxylic acidamide (Example 6, 35, mg, 0.09 mmol). Purification by chromatography(silica gel, 1% methanol saturated with ammonia/9% methanol/CH₂Cl₂)afforded 25 mg (71%) of the title compound. TLC (silica, 1% methanolsaturated with ammonia/9% methanol/CH₂Cl₂): R_(f)=0.13. HPLC (Method A):R_(t)=6.57. MS (ESI+): mass calculated for C₂₂H₁₉N₃O₃, 373.1; m/z found,374.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): δ 8.10 (br s, 1H), 7.97 (d, J=8.3Hz, 2H), 7.71 (br d, J=7.7 Hz, 1H), 7.53 (br s, 1H), 7.47 (d, J=8.2 Hz,2H), 7.20 (d, J=8.7 Hz, 2H), 6.79 (d, J=8.7 Hz, 2H), 5.71 (s, 1H), 3.66(s, 3H).

Example 23

2-[4-(Hydroxy-naphthalen-2-yl-methyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide

The title compound was prepared as described in Example 19 from2-[4-(naphthalene-2-carbonyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide (Example 7, 60 mg, 0.15 mmol). Purification by chromatography(silica gel 1% methanol saturated with ammonia/9% methanol/CH₂Cl₂)afforded 43 mg (72% of the title compound. TLC (silica, 1% methanolsaturated with ammonia/9% methanol/CH₂Cl₂): R_(f)=0.21. HPLC (Method A):R_(t)=0.8 MS (ESI+): mass calculated for C₂₅H₁₉N₃O₂, 393.1; m/z found,394.1 [M+]⁺, ¹H NMR (500 MHz, CD₃OD): δ 8.18 (br s, 1H), 8.08 (d, J=8.4Hz, 2H), 7.92 (s, 1H), 7.84 (d, J=8.9 Hz, 1H), 7.89 (d, J=8.5 Hz, 3H),7.63 (d, J=8.3 Hz, 3H); 7.48-7.41 (m, 3H), 6.02 (s, 1H).

Example 24

2-{4-[(4-Chloro-3-trifluoromethyl-phenyl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide

The title compound was prepared as described in Example 19 from2-[4-(4-chloro-3-trifluoromethyl-benzoyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide (Example 8, 69 mg, 0.15 mmol). Purification by chromatography(silica gel, 1% methanol saturated with ammonia/9% methanol/CH₂Cl₂)afforded 60 mg (87%) of the title compound. TLC (silica, 1% methanolsaturated with ammonia/9% methanol/CH₂Cl₂): R_(f)=0.17. HPLC (Method A):R_(t)=7.5. MS (ESI−): mass calculated for C₂₂H₁₅ClF₃N₃O₂, 445.1; m/zfound, 444.5 [M−H]⁻. ¹H NMR (500 MHz, CD₃OD): δ 8.17 (br s, 1H), 8.10(d, J=8.4 Hz, 2H), 7.85 (d, J=1.8 Hz, 1H), 7.81 (br d, J=8.4 Hz, 1H),7.64-7.62 (dd, J=8.3, 1.9 Hz, 2H), 7.59-7.55 (m, 3H), 5.93 (s, 1H).

Example 25

2-{4-[(3-Bromo-4,5-dimethoxy-phenyl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide

The title compound was prepared as described in Example 19 from2-[4-(3-bromo-4,5-dimethoxy-benzoyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide (Example 9, 60 mg, 0.12 mmol). Purification by chromatography(silica gel, 1% methanol saturated with ammonia/19% methanol/CH₂Cl₂)afforded 37 mg (62%) of the title compound. TLC (silica, 1% methanolsaturated with ammonia/9% methanol/CH₂Cl₂): R_(f)=0.18. HPLC (Method A):R_(t)=6.82. MS (ESI+): mass calculated for C₂₃H₂₀BrN₃O₄, 481.1; m/zfound, 482.0/484.0 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): δ8.17 (br s, 1H),8.07 (d, J=8.4 Hz, 2H), 7.82-7.80 (dd, J=8.5, 1.2 Hz, 1H), 7.63 (d,J=7.6 Hz, 1H), 7.57 (d, J=8.3 Hz, 2H), 7.20 (s, 1H), 7.11 (s, 1H), 6.14(s, 1H), 3.82 (s, 3H), 3.80 (s, 3H).

Example 26

2-{4-[(3,4-Dichloro-phenyl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide

The title compound was prepared as described in Example 19 from2-[4-(3,4-dichloro-benzoyl)-phenyl]-1H-benzoimidazole-5-carboxylic acidamide (Example 10, 70 mg, 0.17 mmol). HPLC (Method A): R_(t)=7.29. MS(ESI+): mass calculated for C₂₁H₁₅Cl₂N₃O₂, 411.1; m/z found, 412.2[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): δ 13.58 (br s, 1H), 8.23 (d, J=8.2Hz, 2H), 8.16 (br s, 1H), 8.01 (br s, 1H), 7.77 (dd, J=8.1 Hz, 1H), 7.68(d, J=1.8 Hz, 1H), 7.59 (d, J=8.3 Hz, 2H), 7.57 (d, J=8.3 Hz, 2H),7.41-7.39 (dd, J=8.4, 1.8 Hz, 1H), 7.24 (br s, 1H), 6.36 (d, J=4.1 Hz,1H), 5.83 (d, J=3.8 Hz, 1H).

Example 27

2-{4-[(3,4-Dimethyl-phenyl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide

The title compound was prepared as described in Example 19 from2-[4-(3,4-dimethyl-benzoyl)-phenyl]-1H-benzoimidazole-5-carboxylic acidamide (Example 11, 60 mg, 0.16 mmol). Purification by chromatography(silica gel, 1% methanol saturated with ammonia/9% methanol/CH₂Cl₂)afforded 50.2 mg (84%) of the title compound. TLC (silica, 1% methanolsaturated with ammonia/9% methanol/CH₂Cl₂): R_(f)=0.13. HPLC (Method A):R_(t)=7.09. MS (ESI+): mass calculated for C₂₃H₂₁N₃O₂, 371.2; m/z found,372.2 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): δ 8.17 (br s, 1H), 8.05 (d, J=8.4Hz, 2H), 7.81-7.79 (dd, J=8.4, 1.4 Hz, 1H), 7.62 (br d, J=7.6 Hz, 1H),7.56 (d, J=8.1 Hz, 2H), 7.15 (s, 1H), 7.10-7.06 (m, 2H), 5.78 (s, 1H),2.23 (s, 3H), 2.22 (s, 3H).

Example 28

2-{4-[(4-Ethyl-phenyl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide

The title compound was prepared as described in Example 19 from2-[4-(4-ethyl-benzoyl)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide(Example 12, 60 mg, 0.16 mmol). Purification by chromatography (silicagel, 1% methanol saturated with ammonia/9% methanol/CH₂Cl₂) afforded 52mg (87%) of the title compound. TLC (silica, 1% methanol saturated withammonia/9% methanol/CH₂Cl₂): R_(f)=0.17. HPLC (Method A): R_(t)=7.17. MS(ESI+): mass calculated for C₂₃H₂₁N₃O₂, 371.2; m/z found, 372.1 [M+H]⁺.¹H NMR (500 MHz, CD₃OD): δ8.17 (br s, 1H), 8.06 (d, J=8.4 Hz, 2H),7.81-7.79 (dd, J=8.5, 1.6 Hz, 1H), 7.62 (br d, J=8.3 Hz, 1H), 7.56 (d,J=8.1 Hz, 2H), 7.29 (d, J=8.1 Hz, 2H), 7.16 (d, J=8.2 Hz, 2H), 5.82 (s,1H), 2.62-2.58 (q, J=7.6 Hz, 2H), 1.19 (t, J=7.6 Hz, 3H).

Example 29

2-[4-(Benzo[1,3]dioxol-5-yl-hydroxy-methyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide

The title compound was prepared as described in Example 19 from2-[4-(benzo[1,3]dioxole-5-carbonyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide (Example 13, 40 mg, 0.1 mmol). Purification by chromatography(silica gel, 1% methanol saturated with ammonia/9%-methanol/CH₂Cl₂)afforded 29 mg (71%) of the title compound. TLC (silica, 1% methanolsaturated with ammonia/9% methanol/CH₂Cl₂): R_(f)=0.16. HPLC (Method A):R_(t)=6.78. MS (ESI+): mass calculated for C₂₂H₁₇N₃O₄, 387.1; m/z found,388.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): δ 8.17 (br s, 1H), 8.06 (d, J=8.4Hz, 2H), 7.82-7.80 (dd, J=8.5, 1.6 Hz, 1H), 7.63 (d, J=8.5 Hz, 1H), 7.56(d, J=8.2 Hz, 2H), 6.89-6.87 (dd, J=8.1, 1.6 Hz, 1H), 6.86 (d, J=1.6 Hz,1H), 6.77 (d, J=8.0 Hz, 1H), 5.91-5.89 (m, 2H), 5.77 (s, 1H).

Example 30

2-{4-[(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide

The title compound was prepared as described in Example 19 from2-[4-(2,3-dihydro-benzo[1,4]dioxine-6-carbonyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide (Example 14, 60 mg, 0.15 mmol). Purification bychromatography (silica gel, 1% methanol saturated with ammonia/9%methanol/CH₂Cl₂) afforded 46.6 mg (78%) of the title compound. TLC(silica, 1% methanol saturated with ammonia/9% methanol/CH₂Cl₂):R_(f)=0.16 HPLC (Method A): R_(t)=6.74. MS (ESI+): mass calculated forC₂₃H₁₉N₃O₄, 401.1°; m/z found, 402.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): δ8.17 (br s, 1H), 8.06 (d, J=8.3 Hz, 2H), 7.82-7.80 (dd, J=8.4, 1.4 Hz,1H), 7.63 (br d, J=8.0 Hz, 1H) 7.55 (d, J=8.3 Hz, 2H), 6.86 (d, J=1.9Hz, 1H), 6.84-6.82 (dd, J=8.3, 1.9 Hz, 1H), 6.77 (d, J=8.3 Hz, 1H), 5.74(s, 1H), 4.19 (s, 4H).

Example 31

2-[4-(Hydroxy-quinolin-3-yl-methyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide

The title compound was prepared as described in Example 19 from2-[4-(quinoline-3-carbonyl)-phenyl]-1H-benzoimidazole-5-carboxylic acidamide (Example 15, 40 mg, 0.1 mmol). Purification by chromatography(silica gel, 1% methanol saturated with ammonia/9% methanol/CH₂Cl₂)afforded 13.9 mg, (35%) of the title compound. HPLC (Method A):R_(t)=6.04. MS (ESI+): mass calculated for C₂₄H₁₈N₄O₂, 394.1; m/z found,395.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): δ 8.78 (d, J=2.1 Hz, 1H), 8.26(d, J=1.0 Hz, 1H), 8.25 (br s, 1H), 8.02 (d, J=8.4 Hz, 2H), 7.90 (d,J=8.5 Hz, 1H), 7.84 (d, J=8.2 Hz, 1H), 7.71 (d, J=8.3 Hz, 1H), 7.66-7.63(m, 1H), 7.58 (d, J=8.3 Hz, 2H), 7.52 (br s, 1H), 7.51-7.49 (m, 1H),6.03 (s, 1H).

Example 32

2-[4-(Hydroxy-pyridin-4-yl-methyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide

The title compound was prepared as described in Example 19 from2-[4-(pyridine-4-carbonyl)-phenyl]-1H-benzoimidazole-5-carboxylic acidamide (Example 16; 15 mg, 0.04 mmol). Purification by chromatograph(silica gel, 1% methanol saturated with ammonia/9% methanol/CH₂Cl₂)afforded 10.2 mg (68%) of the title compound. TLC (silica, 1% methanolsaturated with ammonia/9% methanol/CH₂Cl₂): R_(f)=0.09. HPLC (Method A):R_(t)=5.64. MS (ESI+): mass calculated for C₂₀H₁₆N₄O₂, 344.1; m/z found,345.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): δ 8.39 (d, J=6.2 Hz, 2H), 8.12(br s, 1H), 8.00 (d, J=8.3 Hz, 2H), 7.75 (br s, 1H), 7.51 (d, J=8.3 Hz,2H), 7.42 (d, J=6.0 Hz, 2H), 5.79 (s, 1H).

Example 33

2-[4-(Cyclohexyl-hydroxy-methyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide

The title compound was prepared as described in Example 19 from2-(4-cyclohexanecarbonyl-phenyl)-1H-benzoimidazole-5-carboxylic acidamide (Example 17, 90 mg, 0.26 mmol). Purification by chromatography(silica gel, 1% methanol saturated with ammonia/9% methanol/CH₂Cl₂)afforded 31 mg (34%) of the title compound. TLC (silica, 1% methanolsaturated with ammonia/9% methanol/CH₂Cl₂): R_(f)=0.2. MS (ESI+): masscalculated for C₂₁H₂₃N₃O₂, 349.2; m/z found, 350.3 [M+H]⁺. ¹H NMR (500MHz, CD₃OD): δ 8.18 (br s, 1H), 8.07 (d, J=8.3 Hz, 2H), 7.81 (d, J=8.3Hz, 1H), 7.63 (br s, 1H), 7.49 (d, J=8.3 Hz, 2H), 4.40 (d, J=7.0 Hz,1H), 1.99 (d, J=13.1 Hz, 1H), 1.77 (d, J=12.9 Hz, 1H), 1.69-1.60 (m,3H), 1.41 (d, J=12.9 Hz, 1H), 1.28-1.01 (m, 5H).

Example 34

2-[4-(Methoxy-phenyl-methyl)-phenyl]-1H-benzoimidazole-5-carboxylic acidamide

To a solution of2-[4-(hydroxy-phenyl-methyl)-phenyl]-1H-benzoimidazole-5-carboxylic acidamide (Example 19, 8.7 mg, 0.02 mmol) in chloroform (1.0 mL) was addedconcentrated HCl (0.1 mL). The reaction mixture was stirred at RT for 2h. Organics were removed under reduced pressure, and purification usingpreparative TLC (silica, 1% methanol saturated with ammonia/9%methanol/CH₂Cl₂) afforded 4.2 mg (47%) of the title compound. HPLC(Method A): R_(t)=6.97. MS (ESI+): mass calculated for C₂₂H₁₉N₃O₂,357.1; m/z found, 358.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.18 (br s,1H), 8.08 (d, J=8.2 Hz, 2H), 7.82 (br d, J=8.0 Hz, 1H), 7.64 (br s, 1H),7.56 (d, J=8.3 Hz, 2H), 7.40 (d, J=8.0 Hz, 2H), 7.35 (t, J=7.5 Hz, 2H),7.28-7.25 (m, 1H), 5.39 (s, 1H), 3.40 (s, 3H).

Example 35

2-[4-(4-Chloro-benzyl)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide

To a solution of2-{4-[(4-chloro-phenyl)-hydroxy-methyl]-phenyl}-1-H-benzoimidazole-5-carboxylicacid amide (Example 20, 50 mg, 0.13 mmol) in TFA (5.0 mL) was addedsodium borohydride (211 mg, 4.2 equiv), and the reaction mixture wasstirred at RT for 16 h. Water (5.0 mL) was added to the mixture, whichwas then adjusted to pH 9 with 1 N NaOH. The precipitate was collectedby filtration and washed with H₂O (20 mL). Purification bychromatography (silica gel, 1% methanol saturated with ammonia/9%methanol/CH₂Cl₂) afforded 39 mg (81%) of the title compound. HPLC(Method A): R_(t)=7.64. MS (ESI+): mass calculated for C₂₁H₁₆ClN₃O,361.1; m/z found, 362.2 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): δ 8.23 (d,J=1.4 Hz, 1H), 8.06 (d, J=8.2 Hz, 2H), 7.94-7.92 (dd, J=8.5, 1.6 Hz,1H), 7-0.74 (d, J=8.5 Hz, 1H), 7.48 (d, J=8.2 Hz, 2H), 7.31 (d, J=8.4Hz, 2H), 7.25 (d, J=8.4 Hz, 2H), 4.09 (s, 2H).

Example 36

2-(4-Naphthalen-2-ylmethyl-phenyl)-1H-benzoimidazole-5-carboxylic acidamide

The title compound was prepared as described in Example 35 from2-[4-(hydroxy-naphthalen-2-yl-methyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide (Example 23, 20 mg, 0.05 mmol). Purification bychromatography (silica gel, 1% methanol saturated with ammonia/9%methanol/CH₂Cl₂) afforded 19 mg (100%) of the title compound. TLC(silica, 1% methanol saturated with ammonia/9% methanol/CH₂Cl₂):R_(f)=0.33. HPLC (Method A): R_(t)=7.80. MS (ESI+): mass calculated forC₂₅H₁₉N₃O, 377.2; m/z found, 378.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): δ8.17 (dd, J=1.5, 0.5 Hz, 1H), 7.97 (d, J=8.4 Hz, 2H), 7.93-7.91 (dd,J=8.5, 1.5 Hz, 1H), 7.71-7.67 (m, 4H), 7.63 (s, 1H), 7.49 (d, J=8.4 Hz,2H), 7.37-7.37 (m, 2H), 7.27-7.25 (dd, J=8.4, 1.6 Hz, 1H), 4.18 (s, 2H).

Example 37

2-[4-(3,4-Dimethyl-benzyl)-phenyl]-1H-benzoimidazole-5-carboxylic acidamide

The title compound was prepared as described in Example 35 from2-{4-[(3,4-dimethyl-phenyl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide (Example 27, 14 mg, 0.03 mmol). Purification bychromatography (silica gel, 1% methanol saturated with ammonia/9%methanol/CH₂Cl₂) afforded 11.1 mg (83%) of the title, compound. TLC(silica, 1% methanol saturated with ammonia/9% methanol/CH₂Cl₂):R_(f)=0.39. HPLC (Method A): R_(t)=8.11. MS (ESI+): mass calculated forC₂₃H₂₁N₃O, 855.2; m/z found, 356.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): δ8.17 (s, 1H), 8.04 (d, J=8.2 Hz, 2H), 7.81 (br d, J=8.2 Hz, 1H), 7.63(br s, 1H), 7.40 (d, J=8.2 Hz, 2H), 7.05 (d, J=7.71 Hz, 1H), 7.02 (s,1H), 6.96 (d, J=7.6 Hz, 1H), 3.97 (s, 2H), 2.22 (d, J=4.1 Hz, 6H).

Example 38

2-[4-(4-Ethyl-benzyl)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide

The title compound was prepared as described in Example 35 from2-{4-[(4-ethyl-phenyl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide (Example 28, 26.5 mg, 0.07 mmol). Purification bychromatography (silica gel, 1% methanol saturated with ammonia/9%methanol/CH₂Cl₂) afforded 19 mg (76%) of the title compound. TLC(silica, 1% methanol saturated with ammonia/9% methanol/CH₂Cl₂):R_(f)=0.41. HPLC (Method A): R_(t)=7.84. MS (ESI+): mass calculated forC₂₃H₂₁N₃O, 355.2; m/z found, 356.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): δ8.16 (d, J=1.5 Hz, 1H), 7.94 (d, J=8.4 Hz, 2H), 7.89 (dd, J=8.6, 1.6 Hz,1H), 7.67 (d, J=8.5 Hz, 1H), 7.41 (d, J=8.4 Hz, 2H), 7.05-7.04 (m, 4H),3.96 (s, 2H), 2.53-2.48 (q, J=7.6 Hz, 2H), 1.10; (t, J=7.6 Hz, 3H).

Example 39

2-[4-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-1H-benzoimidazole-5,carboxylic acid amide

The title compound was prepared as described in Example 35 from2-{4-[(2,3-dihydrobenzo[1,4]dioxin-6-yl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide (Example 30, 15.3 mg, 0.04 mmol). Purification bychromatography (silica gel, 1% methanol saturated with ammonia/9%methanol/CH₂Cl₂) afforded 12.1 mg: (83%) of the title compound. TLC(silica, 1% methanol saturated with ammonia/9% methanol/CH₂Cl₂):R_(f)=0.30. HPLC (Method A): R_(t)=7.19. MS (ESI+) mass calculated forC₂₃H₁₉N₃O₃, 385.1; m/z found, 386.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): δ8.10 (d, J=1.4 Hz, 1H), 7.92 (d, J=8.3 Hz, 2H), 7.79-7.77 (dd, J=8.5,1.6 Hz, 1H), 7.59 (d, J=8.5 Hz, 1H), 7.32 (d, J=8.3 Hz, 2H), 6.65 (d,J=8.9 Hz, 1H), 6.59-6.57 (m, 2H), 4.09 (s 1H) 3.84 (s, 2H).

Example 40

2-(4-Cyclohexylmethyl-phenyl)-1H-benzoimidazole-5-carboxylic acid amide

The title compound was prepared as described in Example 35 from,2-[4-(cyclohexyl-hydroxy-methyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide (Example 33, 11.4 mg, 0.03 mmol). Product was isolated as aTFA salt (7.3 mg, 50%). HPLC (Method A): R_(t)=8.46. MS (ESI+): masscalculated for C₂₁H₂₃N₃O, 333.2, m/z found, 446.3 [M+H]⁺+TFA. ¹H NMR(500 MHz, CD₃OD): δ 8.19 (d, J=1.5 Hz, 1H), 8.08 (d, J=8.4 Hz, 2H),7.92-7.89 (d, J=8.6, 1.5 Hz, 1H), 7.69 (d, J=8.5 Hz, 1H), 7.57 (d, J=8.4Hz, 2H), 5.69 (d, J=7.9 Hz, 1H), 1.96-1.91 (m, 1H), 1.87-1.82 (m, 1H),1.73-1.69 (m, 1H), 1.66-1.59 (m, 2H), 1.35-1.32 (m, 1H), 1.20-0.95 (m,6H).

Example 41

2-{4-[1-(4-Chloro-phenyl)-vinyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide

A. 1-(4-Chloro-phenyl)-1-(4-1,3]dioxan-2-yl-phenyl)-ethanol. To asolution of 1-(4-chloro-phenyl)-ethanone (582 mg, 3.7 mmol) in anhydrousTHF (25 mL), cooled to −78° C., was added4-(1,3-dioxan-2-yl)phenylmagnesium bromide (16 mL, 0.25 M in THF)dropwise. The reaction mixture was stirred 1 h at −78° C. then wasquenched with saturated aqueous NH₄Cl (50 mL). The resulting mixture wasextracted with Et₂O (2×100 mL), and the combined extracts were washedwith H₂O (100 mL) then brine (100 mL), and dried (MgSO₄). Solvent wasremoved under reduced pressure. Purification of the residue bychromatography (silica gel, 50% ethyl acetate/hexanes) afforded 627 mg(52%) of the title compound. TLC (silica, 50% ethyl acetate/hexanes):R_(f)=0.42. HPLC (Method A): R_(t)=10.16. ¹H NMR (500 MHz, CD₃OD): δ7.41 (d, J=8.3 Hz, 2H), 7.35 (d, J=8.5 Hz, 2H), 7.27 (d, J=8.7 Hz, 2H),7.21 (d, J=8.7 Hz, 2H), 5.46 (s, 1H), 4.24-4.20 (m, 2H), 3.98-3.92 (m,2H), 2.94 (s, 1H), 2.23-2.14 (m, 1H), 1.84 (s, 3H), 1.43-1.39 (m, 1H).

B. 4-[1-(4-Chloro-phenyl)-vinyl]-benzaldehyde. This compound wasprepared as described in Example 3 substituting1-(4-chloro-phenyl)-1-(4-[1,3]dioxan-2-yl-phenyl)-ethanol (150 mg, 0.47mmol) for 4-(2-phenyl-[1,3]dioxolan-2-yl)-benzaldehyde in Step A. Thetitle compound (100 mg, 88%) was used without purification in the nextreaction. TLC (silica, 50% ethyl acetate/hexanes): R_(f)=0.66. HPLC(Method A): R_(t)=10.65. ¹H NMR (500 MHz, CD₃OD): δ 10.02 (s, 1H), 7.86(d, J=8.2 Hz, 2H), 7.47 (d, J=8.2 Hz; 2H), 7.32 (d, J=8.6 Hz, 2H), 7.24(d, J=8.6 Hz, 2H), 5.58 (s, 1H), 5.57 (s, 1H).

C.2-{4-[1-(4-Chloro-phenyl)-vinyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide. This compound was prepared as described in Example 1substituting 4-[1-(4-chloro-phenyl)-vinyl]-benzaldehyde (100 mg, 0.4mmol) for 4-(2-phenyl-[1,3]dioxolan-2-yl)-benzaldehyde in Step C.Purification by chromatography (silica gel, 1% methanol saturated withammonia/9% methanol/CH₂Cl₂) afforded the title compound (60 mg, 39%).TLC (silica, 1% methanol saturated with ammonia/9% methanol/CH₂Cl₂):R_(f)=0.29. HPLC (Method A): R_(t)=7.89. MS (ESI+): mass calculated forC₂₂H₁₆ClN₃O, 373.1, m/z found, 373.6 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): δ8.10 (br s, 1H), 8.02 (d, J=8.5 Hz, 2H), 7.74 (br d, J=8.5 Hz, 1H), 7.58(br s, 1H), 7.42 (d, J=8.5 Hz, 2H), 7.29 (d, J=8.7 Hz, 2H), 7.24 (d,J=8.7 Hz, 2H), 5.53 (s, 1H), 5.48 (s, 1H).

Example 42

2-{4-[1-(4-Chloro-phenyl)-ethyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide

A flask-containing a solution of2-{4-[1-(4-chloro-phenyl)-vinyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide (Example 41, 30 mg, 0.08 mmol) in 1:1 ethanol/ethyl acetate(6.0 mL) was charged with N₂ and evacuated (3×). Palladium on carbon (10wt %) was added to the solution, and the flask was charged with H₂ andevacuated (3×), and then maintained at ˜1 atm H₂ for 2.5 h. The flaskwas evacuated and then charged with N₂. The reaction mixture wasfiltered through a pad of Celite®, which was washed with ethanol (50mL), ethyl acetate (50 mL) and then methanol (2×50 mL). The filtrate wasconcentrated under reduced pressure. Purification of the residue bychromatography (silica gel, 1% methanol saturated with ammonia/9%methanol/CH₂Cl₂) afforded the title compound (21 mg, 68%). TLC (silica,1% methanol saturated with ammonia/9/% methanol/CH₂Cl₂): R_(f)=0.35. MS(ESI+): mass calculated for C₂₂H₁₈ClN₃O, 375.1, m/z found, 376.1.[M+H]⁺. ¹H NMR (500 MHz, CD₃OD): δ 8.16 (br s, 1H), 8.04 (d, J=8.4 Hz,2H), 7.81 (d, J=8.3 Hz, 1H), 7.62 (br s, 1H), 7.43 (d, J=8.3 Hz, 2H),7.30-7.26 (m, 4H), 4.27-4.24 (m, 1H), 1.67 (d, J=7.2 Hz, 3H).

Example 43

2-{4-[(4-Chloro-phenyl)-piperazin-1-yl-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide

To a suspension of2-{4-[(4-chloro-phenyl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide (Example 20, 20.0 mg; 0.05 mmol) in CH₂Cl₂(10 mL) was addedthionyl chloride (0.04 mL, 0.06 mmol), and the mixture was stirred at RTfor 1 h. Solvent was removed under reduced pressure, and the residue wasdried under high vacuum. The crude product was dissolved in acetonitrile(10 mL). Piperazine (21 mg, 0.24 mmol) was added, and the mixture washeated to reflux for 12 h. Solvent was removed under reduced pressure,and purification of the residue by chromatography (silica gel, 1%methanol saturated with ammonia/9% methanol/CH₂Cl₂) afforded 17 mg (77%)of the title compound. HPLC (Method A): R_(t)=6.44. MS (ESI−): masscalculated for C₂₅H₂₄ClN₅, 445.2; m/z found, 444.6 [M−H]⁻. ¹H NMR (500MHz, CD₃OD), δ 8.17 (br s, 1H), 8.09 (d, J=8.4 Hz, 2H), 7.82-7.80 (dd,J=8.5, 1.5 Hz, 1H), 7.66 (d J=8.4 Hz, 2H), 7.63 (br s, 1H), 7.50 (d,J=8.5 Hz, 2H), 7.35 (d, J=8.5 Hz, 2H), 4.56 (s, 1H), 3.31-3.27 (m, 8H).

Example 44

2-(4-{(4-Chloro-phenyl)-[methyl-(2-methylamino-ethyl)-amino]-methyl}-phenyl)-1H-benzoimidazole-5-carboxylicacid amide

The title compound was prepared as described in Example 43 substitutingN,N′-dimethyl-ethane-1,2-diamine for piperazine. HPLC (Method A):R_(t)=6.73. MS (ESI+): mass calculated for C₂₅H₂₆ClN₅O, 447.2; m/zfound, 448.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): δ 8.07 (d, J=1.1 Hz, 1H),7.96 (d, J=8.3 Hz, 2H), 7.72-7.70 (dd, J=8.5, 1.5 Hz, 1H), 7.54 (d,J=7.9 Hz, 2H), 7.52 (s, 1H), 7.38 (d, J=8.5 Hz, 2H), 7.20 (d, J=8.5 Hz,2H), 4.40 (s, 1H), 2.63 (t, J=6.5 Hz, 2H), 2.43 (t, J=6.4 Hz, 2H), 2.26(s, 3H), 2.10 (s, 3H).

Example 45

2-[4-(Methyl-phenyl-amino)-phenyl]-1H-benzoimidazole-5-carboxylic acidamide

A. (4-Bromo-phenyl)-methyl-phenyl-amine. To a cooled, solution (0° C.)of methyl-diphenyl-amine (1.17 g, 6.4 mmol) in anhydrous CH₂Cl₂ (20 mL)was slowly added N-bromosuccinimide (1.15 g, 6.4 mmol) dissolved inCH₂Cl₂ (20 mL). The reaction mixture was stirred for 2 h at 0° C. andthen refrigerated overnight. Solvent was removed under reduced pressure,and the residue was purified by chromatography (silica gel, 10% ethylacetate/hexanes) to afford 1.38 g (82%) of the title compound. ¹H NMR(500 MHz, CDCl₃): δ7.32 (d, J=9.0 Hz, 2H), 7.29 (d, J=8.6 Hz, 2H),7.06-7.04 (dd, J=8.7, 1.1 Hz, 2H), 7.03-7.02 (m, 1H), 6.83 (d, J=8.9 Hz,2H), 3.28 (s, 3H).

B. 4-(Methyl-phenyl-amino)-benzaldehyde. This compound was prepared asdescribed in Example 1 substituting (4-bromo-phenyl)-methyl-phenyl-amine(500 mg, 1.19 mmol) for 2-(4-bromo-phenyl)-2-phenyl-[1,3]dioxolane inStep B. Purification by chromatography (silica gel, 10% ethylacetate/hexanes) afforded the title compound, 381 mg (94%). ¹H NMR (500MHz, CDCl₃): δ 9.76 (s, 1H), 7.69 (d, J=8.9 Hz, 2H), 7.43 (t, J=7.8 Hz,2H), 7.28 (d, J=7.4 Hz, 1H), 7.24-7.22 (dd, J=8.4, 1.2 Hz, 2H), 6.78 (d,J=8.9 Hz, 2H), 3.39 (s, 3H).

C. 2-[4-(Methyl-phenyl-amino)-phenyl]-1H-benzoimidazole-5-carboxylicacid. This compound was prepared as described in Example 1 using4-(methyl-phenyl-amino)-benzaldehyde (380 mg, 1.8 mmol) and3,4-diamino-benzoic acid (273 mg, 1.8 mmol) in Step C. Crude product(528 mg, 85%) was used without further purification. HPLC (Method A):R_(t)=7.38. MS (ESI): mass calculated for C₂₁H₁₇N₃O₂, 343.1; m/z found,344.1 [M+H]⁺, 342.1, [M−H]⁻.

D. 2-[4-(Methyl-phenyl-amino)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide. This compound was prepared as described in Example 2 using2-[4-(methyl-phenyl-amino)-phenyl]-1H-benzoimidazole-5-carboxylic acid(500 mg, 1.4 mmol) in Step D. Purification by chromatography (silicagel, 1% methanol saturated with ammonia/9% methanol/CH₂Cl₂) afforded 329mg (66%) of the title compound. TLC (silica, 1% methanol saturated withammonia/9% methanol/CH₂Cl₂): R_(f)=0.35. HPLC (Method A): R_(t)=7.07. MS(ESI): mass calculated for C₂₁H₁₈N₄O, 342.1, m/z found, 343.2 [M+H]⁺,341.2, [M−H]⁻. ¹H NMR (400 MHz, CD₃OD): δ 8.01 (s, 1H), 7.82 (d, J=8.9Hz, 2H), 7.68-7.65 (dd, J=8.4, 1.6 Hz, 1H), 7.47 (br d, J=8.4 Hz, 1H),7.31 (t, J=7.9 Hz, 2H), 7.14-7.12 (dd, J=8.6, 1.2 Hz, 2H), 7.09 (d,J=7.4 Hz, 1H), 6.83 (d, J=8.9 Hz, 2H), 3.27 (s, 3H).

Example 46

2-(4-Benzylsulfamoyl-phenyl)-1H-benzoimidazole-5-carboxylic acid amide

A. N-Benzyl-4-formyl-benzenesulfonamide. To a solution of4-formylbenzenesulfonyl chloride (200 mg, 0.978 mmol) and benzylamine(105 mg, 0.978 mmol) in anhydrous CH₂Cl₂ (3.3 mL) was addedtriethylamine (198 mg, 1.96 mmol) dropwise. The mixture was stirred atRT for 17 h, and then diluted with saturated aqueous NaHCO₃. The aqueouslayer was extracted with ethyl acetate (X3), and the combined organicextracts were washed with brine and dried (MgSO₄). The solvent wasremoved under reduced pressure, and the residue was purified bychromatography (silica gel, 20% EtOAc/hexanes) to provide 197 mg (73%)of the title compound as a white solid. HPLC (Method C): R_(t)=6.01. MS(ESI): mass calculated for C₁₄H₁₃NO₃S, 275.1; m/z found, 274.2 [M−H]⁻.¹H NMR (400 MHz, CDCl₃): δ 10.1 (s, 1H), 8.05-8.00 (m, 4H), 7.30-7.28(m, 3H), 7.21 (dd, J=2.2, 9.6 Hz, 2H), 5.15 (bt, J=6.0 Hz, 1H), 4.23 (d,J=6.1 Hz, 2H). ¹³C NMR (100 MHz, CDCl₃): δ 191.3, 145.7, 139.2, 136.2,130.6, 129.2, 128.5, 128.3, 128.2, 47.8.

B. 2-(4-Benzylsulfamoyl-phenyl)-1H-benzoimidazole-5-carboxylic acidamide. A solution of N-benzyl-4-formyl-benzenesulfonamide (137 mg, 0.497mmol), 3,4-diamino-benzamide (75 mg, 0.497 mmol), and sodiummetabisulfite (123 mg, 0.646 mmol) in DMF (5 mL) was heated at 60° C.for 14.5 h. After cooling to RT, the reaction mixture was poured intoice-cold saturated aqueous NH₄Cl (25 mL), and the precipitate wascollected by vacuum filtration. Purification by chromatography (silicagel, 10% methanol saturated with NH₃/30% THF/60% CH₂Cl₂) afforded apurple solid, which was triturated with CH₂Cl₂ to provide 36 mg (18%) ofthe title compound as a gray powder. HPLC (Method C): R_(t)=4.55. MS(ESI): mass calculated for C₂₁H₁₈N₄O₃S, 406.1; m/z found, 407.3 [M+H]⁺.¹H NMR (400 MHz, CD₃OD): δ 8.21 (d, J=8.6 Hz, 3H), 7.96 (d, J=8.6 Hz,2H), 7.85 (dd, J=1.6, 8.5 Hz, 1H), 7.67 (d, J=8.5 Hz, 1H), 7.22-7.18 (m,5H), 4.13 (s, 2H).

Example 47

2-[4-(4-Methyl-benzylsulfamoyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide

A. 4-Formyl-N-(4-methyl-benzyl)-benzenesulfonamide. This compound wasprepared as described in Example 46 substituting 4-methylbenzylamine(119 mg, 0.978 mmol) for benzylamine in Step A. The title compound wasobtained as a white solid (162 mg, 57%).

B.2-[4-(4-Methyl-benzylsulfamoyl)-Phenyl]-1H-benzoimidazole-5-carboxylicacid amide. This compound was prepared as described in Example 46substituting 4-formyl-N-(4-methyl-benzyl)-benzene sulfonamide (144-mg,0.497 mmol) for N-benzyl-4-formyl-benzenesulfonamide in Step B. Thetitle compound was obtained as a purple solid (38 mg, 18%). HPLC (MethodC): R_(t)=4.73. MS (ESI): mass calculated for C₂₂H₂₀N₄O₃S, 420.1; m/zfound, 421.4 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.20 (d, J=8.4 Hz, 3H),7.95 (d, J=8.4 Hz, 2H), 7.85 (d, J=8.3 Hz, 1H), 7.66 (bs, 1H), 7.07 (d,J=8.0 Hz, 2H), 7.01 (d, J=7.9 Hz, 2H), 4.08 (s, 2H).

Example 48

2-[4-(4-Methoxy-benzylsulfamoyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide

A. 4-Formyl-N-(4-methoxy-benzyl)-benzenesulfonamide. This compound wasprepared as described in Example 46 Step A, substituting4-methoxybenzylamine (335 mg, 2.44 mmol) for benzylamine. The titlecompound was obtained as a white solid (686 mg, 92%).

B.2-[4-(4-Methoxy-benzylsulfamoyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide. This compound was prepared as described in Example 46 StepB, substituting 4-formyl-N-(4-methoxy-benzyl)-benzenesulfonamide (202mg, 0.66 mmol) for N-benzyl-4-formyl-benzenesulfonamide. The reactionwas run at 90° C. instead of 60° C. The title compound was obtained as ayellow powder (90 mg, 31%). HPLC (Method C): R_(t)=4.48. MS (ESI): masscalculated for C₂₂H₂₀N₄O₄S, 436.1; m/z found, 437.1 [M+H]⁺. ¹H NMR (400MHz, C₂D₆SO): δ 8.37 (d, J=8.5 Hz, 2H), 8.21 (m, 2H), 7.97 (d, J=8.5 Hz,2H), 7.84 (d, 9.1 Hz, 1H), 7.17 (d, J=8.7 Hz, 1H), 6.84 (d, J=8.7 Hz,2H), 3.69 (s, 2H), 3.41 (s, 3H).

Example 49

2-[4-(4-Chloro-benzylsulfamoyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide

A. N-(4-Chloro-benzyl)-4-formyl-benzenesulfonamide. This compound wasprepared as described in Example 46 substituting 4-chlorobenzylamine(138 mg, 0.978 mmol) for benzylamine in Step A. The title compound wasobtained as a white solid (236 mg, 78%).

B.2-[4-(4-Chloro-benzylsulfamoyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide. This compound was prepared as described in Example 46substituting N-(4-chloro-benzyl)-4-formyl-benzenesulfonamide (155 mg,0.50 mmol) for N-benzyl-4-formyl-benzenesulfonamide in Step B. The titlecompound was obtained as a brown powder (30 mg, 14%). HPLC (Method C):R_(t)=4.78. MS (ESI): mass calculated for C₂₁H₁₇ClN₄O₃S, 440.1; m/zfound, 441.3 [M+H]⁺. ¹H NMR (460 MHz, CD₃OD): δ 8.13-8.11 (m, 3H), 7.86(d, J=8.5 Hz, 2H), 7.75 (dd, J=1.6, 8.5 Hz, 1H), 7.58 (d, J=8.5 Hz, 1H),7.10 (s, 4H), 4.01 (s, 2H).

Example 50

2-[4-(3,4-Dichloro-benzylsulfamoyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide

A. N-(3,4-Dichloro-benzyl)-4-formyl-benzenesulfonamide. This compoundwas prepared as described in Example 46 substituting3,4-dichlorobenzylamine (172 mg, 0.978 mmol) for benzylamine in Step A.The title compound was obtained as a white solid, 216 mg (64%).

B.2-[4-(3,4-Dichloro-benzylsulfamoyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide. This compound was prepared as described in Example 46substituting N-(3,4-dichloro-benzyl)-4-formyl-benzenesulfonamide (171mg, 0.497 mmol) for N-benzyl-4-formyl-benzenesulfonamide in Step B. Thetitle compound was obtained as a gray powder (59 mg, 25%). HPLC (MethodC): R_(t)=4.91. MS (ESI): mass calculated for C₂₁H₁₆Cl₂N₄O₃S, 474.0; m/zfound, 475.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.24-8.22 (m, 3H), 7.95(d, J=8.5 Hz, 2H), 7.86 (d, J=9.3 Hz, 1H), 7.69 (d, J=8.5 Hz, 1H),7.37-7.32 (m, 2H), 7.16 (d, J=2.0 Hz, 1H), 4.14 (s, 2H).

Example 51

2-[4-(Benzyl-methyl-sulfamoyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide

A. N-Benzyl-4-formyl-N-methyl-benzenesulfonamide. This compound wasprepared as described in Example 46, Step A, substitutingN-methylbenzylamine (296 mg, 2.44 mmol) for benzylamine. The titlecompound was obtained as a white solid (675 mg, 96%).

B. 2-[4-(Benzyl-methyl-sulfamoyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide. This compound was prepared as described in Example 46 StepB, substituting N-benzyl-4-formyl-N-methyl-benzenesulfonamide (171 mg,0.497 mmol) for N-benzyl-4-formyl-benzenesulfonamide. The reaction wasrun at 90° C. instead of 60° C. The title compound was obtained as anoff-white powder (37 mg, 13%). HPLC (Method C): R_(t)=4.84. MS (ESI):mass calculated for C₂₂H₂₀N₄O₃S, 420.1; m/z found, 421.1 [M+H]⁺. ¹H NMR(400 MHz, C₂D₆SO): δ 8.47 (d, J=8.5 Hz, 2H), 8.23 (bs, 1H), 8.07 (d,J=8.5 Hz, 3H), 7.85 (d, J=8.5 Hz, 1H), 7.69 (d, J=8.5 Hz, 1H), 7.39-7.32(m, 5H), 4.22 (s, 2H), 2.61 (s, 3H).

Example 52

2-[4-(Tetrahydro-pyran-4-carbonyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide

The title compound was prepared as described in Example 4 substitutingtetrahydro-pyran-4-carbaldehyde for 4-chloro-benzaldehyde in Step A. TLC(silica, 1% methanol saturated with ammonia/9% methanol/CH₂Cl₂):R_(f)=0.27. HPLC (Method A): R_(t)=6.27. MS, (ESI+): mass calculated forC₂₀H₁₉N₃O₃, 349.1, m/z found, 350.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): δ8.17 (d, J=8.4 Hz, 3H), 8.10 (d, J=8.4 Hz, 2H), 7.82-7.80 (dd, J=8.4,1.3 Hz, 1H), 7.63 (br d, J=8.1 Hz, 1H), 4.00-3.97 (m, 2H), 3.68-3.58 (m,3H), 1.79-1.70 (m, 4H).

Example 53

2-[4-(Thiophene-2-carbonyl)-phenyl]-1H-benzoimidazole-5-carboxylic acidamide

The title compound was prepared as described in Example 4 substitutingthiophene-2-carbaldehyde for 4-chloro-benzaldehyde in Step A. TLC(silica, 1% methanol saturated with ammonia/9% methanol/CH₂Cl₂):R_(f)=0.26. HPLC (Method A): R_(t)=6.90. MS (ESI+): mass calculated forC₁₉H₁₃N₃O₂S, 347.0; m/z found, 348.0 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): δ8.17 (d, J=8.4 Hz, 2H), 8.12 (br s, 1H), 7.92 (d, J=8.4 Hz, 2H),7.87-7.86 (dd, J=5.0, 1.0 Hz, 1H), 7.75 (d, J=8.3 Hz, 1H), 7.68-7.67(dd, J=3.8, 1.0 Hz, 1H), 7.58 (br s, 1H), 7.18-7.16 (dd, J=4.9, 3.8 Hz,1H).

Example 54

2-[4-(6-Chloro-benzo[1,3]dioxole-5-carbonyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide

The title compound was prepared as described in Example 4 substituting6-chloro-benzo[1,3]dioxole-5-carbaldehyde for 4-chloro-benzaldehyde inStep A. TLC (silica, 1% methanol saturated with ammonia/9%methanol/CH₂Cl₂): R_(f)=0.37. HPLC (Method A): R_(t)=7.47. MS (ESI+):mass calculated for C₂₂H₁₄ClN₃O₄, 419.1; m/z found, 420.2, 422.2 [M+H]⁺.¹H NMR (500 MHz, CD₃OD): δ 8.15 (d, J=8.5 Hz, 2H), 8.14 (br s, 1H), 7.85(d, J=8.6 Hz, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.59 (br s, 1H), 6.93 (s,1H), 6.86 (s, 1H), 6.02 (s, 2H).

Example 55

2-[4-(2-Chloro-benzoyl)-phenyl]-1H-benzoimidazole-5-carboxylic acidamide

The title compound was prepared as described in Example 4 substituting2-chloro-benzaldehyde for 4-chloro-benzaldehyde in Step A. TLC (silica,1% methanol saturated with ammonia/9% methanol/CH₂Cl₂): R_(f)=0.31. HPLC(Method A): R_(t)=7.44. MS (ESI+): mass calculated for C₂₁H₁₄ClN₃O₂,375.1; m/z found, 376.3 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): δ 8.16 (d,J=8.4 Hz, 2H), 8.11 (br s, 1H), 7.85 (d, J=8.6 Hz, 2H), 7.75 (br s, 1H),7.59 (br s, 1H), 7.49-7.47 (m, 2H), 7.46-7.35 (m, 2H).

Example 56

2-[4-(2,4-Dichloro-benzoyl)-phenyl]-1H-benzoimidazole-5-carboxylic acidamide

The title compound was prepared as described in Example 4 substituting2,4-dichloro-benzaldehyde for 4-chloro-benzaldehyde in Step A. TLC(silica, 1% methanol saturated with ammonia/9% methanol/CH₂Cl₂):R_(f)=0.28. HPLC (Method A): R_(t)=7.91. MS (ESI+): mass calculated forC₂₁H₁₃Cl₂N₃O₂, 409.0; m/z found, 410.1, 412.2 [M+H]⁺. ¹H NMR (500 MHz,CD₃OD): δ8.17 (d, J=8.6 Hz, 2H), 8.12 (br s, 1H), 7.85 (d, J=8.6 Hz,2H), 7.76-7.74 (dd, J=8.5, 1.5 Hz, 1H), 7.59 (br d, J=8.3 Hz, 1H), 7.56(d, J=1.9 Hz, 1H), 7.45-7.43 (dd, J=8.2, 1.9 Hz, 1H), 7.40 (d, J=8.2 Hz,1H).

Example 57

2-[4-(2-Methoxy-benzoyl)-phenyl]-1H-benzoimidazole-5-carboxylic acidamide

The title compound was prepared as described in Example 4 substituting2-methoxy-benzaldehyde for 4-chloro-benzaldehyde in Step A. HPLC (MethodA): R_(t)=7.16. MS (ESI+): mass calculated for C₂₂H₁₇N₃O₃, 371.1; m/zfound, 372.3 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): δ 8.09 (br s, 1H), 8.06(d, J=8.6° Hz, 2H), 7.75 (d, J=8.6 Hz, 2H), 7.73-7.71 (dd, J=8.5, 1.6Hz, 1H), 7.54 (d, J=8.4 Hz, 1H), 7.45-7.42 (m, 1H), 7.27-7.26 (dd,J=7.5, 1.7 Hz, 1H), 7.02 (d, J=8.3 Hz, 1H), 6.99-6.96 (m, 1H), 3.59 (s,3H).

Example 58

2-[4-(2-Methyl-benzoyl)-phenyl]-1H-benzoimidazole-5-carboxylic acidamide

The title compound was prepared as described in Example 4 substituting2-methyl-benzaldehyde for 4-chloro-benzaldehyde in Step A. TLC (silica,1% methanol saturated with ammonia/9% methanol/CH₂Cl₂): R_(f)=0.26. HPLC(Method A): R_(t)=7.43. MS (ESI+): mass calculated for C₂₂H₁₇N₃O₂,355.1; m/z found, 356.3 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): δ 8.15 (d,J=8.6 Hz, 2H), 8.14 (br s, 1H), 7.84 (d, J=8.6 Hz, 2H), 7.76-7.74 (dd,J=8.5, 1.3 Hz, 1H), 7.60 (br s, 1H), 7.39-7.36 (m, 1H), 7.29-7.22 (m,3H), 2.23 (s, 3H).

Example 59

2-{4-[Hydroxy-(tetrahydro-pyran-4-yl)-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide

The title compound was prepared as described in Example 19 from2-[4-(tetrahydro-pyran-4-carbonyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide (Example 52, 50 mg, 0.14 mmol). Purification bychromatography (silica gel, 1% methanol saturated with ammonia/9%methanol/CH₂Cl₂) afforded 38 mg (76%) of the title compound. TLC(silica, 1% methanol saturated with ammonia/9% methanol/CH₂Cl₂):R_(f)=0.06. HPLC (Method A): R_(t)=5.76. MS (ESI+): mass calculated forC₂₀H₂₁N₃O₃, 351.1; m/z found, 352.2 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): δ8.08 (br s, 1H), 7.99 (d, J=8.2 Hz, 2H), 7.72 (d, J=8.3 Hz, 1H), 7.54(br s, 1H), 7.43 (d, J=8.3 Hz, 2H), 4.33 (d, J=7.0 Hz, 1H), 3.89-3.86(dd, J=11.4, 3.8 Hz, 1H), 3.79-3.76 (dd, J=11.3, 3.3 Hz, 1H), 3.31-3.26(m, 2H), 1.83-1.74 (m, 2H), 1.40-1.25 (m, 2H), 1.15-1.12 (d, J=12.6 Hz,1H).

Example 60

2-[4-(Hydroxy-thiophen-2-yl-methyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide

The title compound was prepared as described in Example 19 from2-[4-(thiophene-2-carbonyl)-phenyl]-1H-benzoimidazole-5-carboxylic acidamide (Example 53, 19 mg, 0.04 mmol). Purification by chromatography(silica gel, 1% methanol saturated with ammonia/9% methanol/CH₂Cl₂)afforded 11 mg (78%) of the title compound. TLC (silica, 1% methanolsaturated with ammonia/9% methanol/CH₂Cl₂): R_(f)=0.17. HPLC (Method A):R_(t)=6.48. MS (ESI+): mass calculated for C₁₉H₁₅N₃O₂S, 349.1; m/zfound, 350.0 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): δ 8.07 (br s, 1H), 8.01(d, J=8.3 Hz, 2H), 7.72 (br d, J=7.9 Hz, 1H), 7.54 (d, J=8.3 Hz, 3H),7.23-7.22 (dd, J=3.9, 2.4 Hz, 1H), 6.85-6.83 (m, 3H).

Example 61

2-{4-[(6-Chloro-benzo[1,3]dioxol-5-yl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide

The title compound was prepared as described in Example 19 from2-[4-(6-chloro-benzo[1,3]dioxole-5-carbonyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide (Example 54, 150 mg, 0.35 mmol). Purification bychromatography (silica gel, 1% methanol saturated with ammonia/9%methanol/CH₂Cl₂) afforded 136 mg (91%) of the title compound. TLC(silica, 1% methanol saturated with ammonia/9% methanol/CH₂Cl₂):R_(f)=0.21. HPLC (Method A): R_(t)=6.88. MS (ESI+): mass calculated forC₂₂H₁₆ClN₃O₄, 421.1; m/z found, 422.2, 424.2 [M+H]⁺. ¹H NMR (500 MHz,CD₃OD): δ 8.06 (br s, 1H), 7.96 (d, J=8.4 Hz, 2H), 7.71 (dd, J=8.4, 1.4Hz, 1H), 7.53 (br s, 1H), 7.45 (d, J=8.2 Hz, 2H), 6.97 (s, 1H), 6.75 (s,1H), 6.06 (s, 1H), 5.85 (s, 1H), 5.85 (s, 1H).

Example 62

2-{4-[(2-Chloro-phenyl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid-amide

The title compound was prepared as described in Example 19 from2-[4-(2-Chloro-benzoyl)-phenyl]-1H-benzoimidazole-5-carboxylic acidamide (Example 55, 125 mg, 0.3 mmol). Purification by chromatography(silica gel, 1% methanol saturated with ammonia/9% methanol/CH₂Cl₂)afforded 114 mg (91%) of the title compound. TLC (silica, 1% methanolsaturated with ammonia/9% methanol/CH₂Cl₂): R_(f)=0.19. HPLC (Method A):R_(t)=6.83. MS (ESI+): mass calculated for C₂₁H₁₆ClN₃O₂, 377.1; m/zfound, 378.3, 380.2 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): δ 8.06 (br s, 1H),7.95 (d, J=8.2 Hz, 2H), 7.70 (d, =8.3 Hz, 1H), 7.59 (d, J=7.8 Hz, 1H),7.52 (br s, 1H), 7.45 (d, J=8.2 Hz, 2H), 7.27-7.24 (m, 2H), 7.17-7.14(m, 1H), 6.14 (s, 1H).

Example 63

2-{4-[(2,4-Dichloro-phenyl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide

The title compound was prepared as described in Example 19 from2-[4-(2,4-dichloro-benzoyl)-phenyl]-1H-benzoimidazole-5-carboxylic acidamide (Example 56, 75 mg, 0.16 mmol). Purification by chromatography(silica gel, 1% methanol saturated with ammonia/9% methanol/CH₂Cl₂)afforded 61 mg (81%) of the title compound. TLC (silica, 1% methanolsaturated with ammonia/9% methanol/CH₂Cl₂): R_(f)=0.27. HPLC (Method A):R_(t)=7.24. MS (ESI+): mass calculated for C₂₁H₁₅Cl₂N₃O₂, 411.1; m/zfound, 412.2, 414.2 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): δ 8.07 (br s, 1H),7.96 (d, J=8.4 Hz, 2H), 7.71-7.69 (dd, J=8.5, 1.6 Hz, 1H), 7.59 (d,J=8.5 Hz, 1H), 7.53 (br d, J=8.3 Hz, 1H), 7.44 (d, J=8.3 Hz, 2H), 7.32(d, J=2.1 Hz, 1H), 7.29-7.27 (dd, 2=8.5, 2.1 Hz, 1H), 6.07 (s, 1H).

Example 64

2-{4-[Hydroxy-(2-methoxy-phenyl)-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide

The title compound was prepared as described in Example 19 from2-[4-(2-methoxy-benzoyl)-phenyl]-1H-benzoimidazole-5-carboxylic acidamide (Example 57, 120 mg, 0.3 mmol). Purification by chromatography(silica gel, 1% methanol saturated with ammonia/9% methanol/CH₂Cl₂)afforded 101 mg (84%) of the title compound. TLC (silica, 1% methanolsaturated with ammonia/9% methanol/CH₂Cl₂): R_(f)=0.13. HPLC (Method A):R_(t)=6.69. MS (ESI+): mass calculated for C₂₂H₁₉N₃O₃, 373.1; m/z found,374.3 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): δ 8.07 (br s, 1H), 7.93 (d, J=8.3Hz, 2H), 7.70 (br d, J=8.2 Hz, 1H), 7.52 (br s, 1H), 7.45 (d, J=8.3 Hz,2H), 7.40-7.38 (dd, J=7.6, 1.5 Hz, 1H), 7.16-7.13 (m, 1H), 6.88-6.84 (m,2H), 6.10 (s, 1H), 3.70 (s, 3H).

Example 65

2-[4-(Hydroxy-o-tolyl-methyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide

The title compound was prepared as described in Example 19 from2-[4-(2-methyl-benzoyl)-phenyl]-1H-benzoimidazole-5-carboxylic acidamide (Example 58, 100 mg, 0.28 mmol). Purification by chromatography(silica gel, 1% methanol saturated with ammonia/9% methanol/CH₂Cl₂)afforded 78 mg 5′ (78%) of the title compound. TLC (silica, 1% methanolsaturated with ammonia/9% methanol/CH₂Cl₂): R_(f)=0.16. HPLC (Method A):R_(t)=6.74. MS (ESI+): mass calculated for C₂₂H₁₉N₃O₂, 357.1; m/z found,358.3[M+H]⁺. ¹H NMR (500 MHz, CD₃OD): δ 8.06 (br s, 1H), 7.95 (d, J=8.3Hz, 2H), 7.70 (d, J=8.3 Hz, 1H), 7.52 (br s, 1H), 7.39 (d, J=8.2 Hz,2H), 7.35 (d, J=7.4 Hz, 1H), 7.11-7.02 (m, 3H), 5.93 (s, 1H), 2.17 (s,3H).

Example 66

2-[4-(6-Chloro-benzo[1,3]dioxol-5-ylmethyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide

The title compound was prepared as described in Example 35 from2-{4-[(6-chloro-benzo[1,3]dioxol-5-yl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide (Example 61, 53 mg, 0.12 mmol). Purification bychromatography (silica gel, 1% methanol saturated with ammonia/9%methanol/CH₂Cl₂) afforded 34 mg (68%) of the title compound. TLC(silica, 1% methanol saturated with ammonia/9% methanol/CH₂Cl₂):R_(f)=0.38. HPLC (Method A): R_(t)=7.28. MS (ESI+): mass calculated forC₂₂H₁₆ClN₃O₃, 405.1, m/z found, 406.2, 408.3 [M+H]⁺. ¹H NMR (500 MHz,CD₃OD): δ 8.18 (br s, 1H), 7.95 (d, J=8.3 Hz, 2H), 7.93 (d, J=1.6 Hz,1H), 7.70 (d, J=8.6 Hz, 1H), 7.42 (d, J=8.4 Hz, 2H), 6.82 (s, 1H), 6.74(s, 1H), 5.88 (s, 2H), 4.06 (s, 2H).

Example 67

2-[4-(2-Methoxy-benzyl)-phenyl]-1H-benzoimidazole-5-carboxylic acidamide

The title compound was prepared as described in Example 35 from2-{4[hydroxy-(2-methoxy-phenyl)-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide (Example 64, 30 mg, 0.08 mmol). Purification bychromatography (silica gel, 1% methanol saturated with ammonia/9%methanol/CH₂Cl₂) afforded 20 mg (71%) of the title compound. HPLC(Method A): R_(t)=7.46. MS (ESI+): mass calculated for C₂₂H₁₉N₃O₂,357.1, m/z found, 358.3 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): δ 8.06 (br s,1H), 7.88 (d, J=8.4 Hz, 2H), 7.71-7.69 (dd, J=8.5, 1.7. Hz, 1H), 7.51(d, J=8.4 Hz, 1H), 7.26 (d, J=8.4 Hz, 2H), 7.12-7.08 (td, J=8.2, 1.7 Hz,1H), 7.05-7.03 (dd, J=7.4, 1.6 Hz, 1H), 6.84 (d, J=8.2 Hz, 1H),6.79-6.76 (td, J=7.4, 1.5 Hz, 1H), 3.91 (s, 2H), 3.69 (s, 3H).

Example 68

2-[4-(2-Methyl-benzyl)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide

The title compound was prepared as described in Example 35 from2-[4-(hydroxy-o-tolyl-methyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide (Example 65, 11 mg, 0.03 mmol). Product was isolated as a TFAsalt (7 mg, 70%). HPLC (Method A): R_(t)=7.93. MS (ESI+): masscalculated for C₂₂H₁₉N₃O, 341.1, m/z found, 342.3 [M+H]⁺. ¹H NMR (500MHz, CD₃OD): δ 8.06 (br s, 1H), 7.91 (d, J=8.3 Hz, 2H), 7.71 (d, J=8.2Hz, 1H), 7.53 (br s, 1H), 7.20 (d, J=8.4 Hz, 2H), 7.08-7.02 (m, 4H),3.99 (s, 2H), 2.13 (S, 3H).

Example 69

2-[4-(2-Methyl-benzylsulfamoyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide

A. 4-Formyl-N-(2-methyl-benzyl)-benzenesulfonamide. This compound wasprepared as described in Example 46 substituting 2-methylbenzylamine(119 mg, 0.978 mmol) for benzylamine in Step A. The title compound wasobtained as a white solid, 260 mg (92%).

B.2-[4-(2-Methyl-benzylsulfamoyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide. This compound was prepared as described in Example 46substituting 4-formyl-N-(2-methyl-benzyl)-benzenesulfonamide (172 mg,0.662 mmol) for N-benzyl-4-formyl-benzenesulfonamide in Step B. Thetitle compound was obtained as a beige solid, 81 mg (29%). HPLC (MethodC): R_(t)=4.61. MS (ESI): mass calculated for C₂₂H₂₀N₄O₃S, 420.1; m/zfound, 421.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 8.41 (d, J=8.4 Hz,2H), 8.11 (bm, 3H), 7.86 (d, J=8.1 Hz, 1H), 7.69 (bs, 1H), 7.37 (bs,1H), 7.23 (d, J=6.8 Hz, 1H), 7.16 (m, 3H), 4.03 (s, 2H), 2.24 (s, 3H).

Example 70

2-[4-(3-Methyl-benzylsulfamoyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide

A. 4-Formyl-N-(3-methyl-benzyl)-benzenesulfonamide. This compound wasprepared as described in Example 46 substituting 3-methylbenzylamine(119 mg, 0.978 mmol) for benzylamine in Step A. The title compound wasobtained as a white solid, 250 mg (88%).

B.2-[4-(3-Methyl-benzylsulfamoyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide. This compound was prepared as described in Example 46substituting 4-formyl-N-(3-methyl-benzyl)-benzenesulfonamide (172 mg,0.662 mmol) for N-benzyl-4-formyl-benzenesulfonamide in Step B. Thetitle compound was obtained as a beige solid, 72 mg (26%). HPLC (MethodC): R_(t)=4.63. MS (ESI): mass calculated for C₂₂H₂₀N₄O₃S, 420.1; m/zfound, 421.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 8.36 (d, J=8.5 Hz,2H), 8.04 (bs, 1H), 7.96 (d, J=8.5 Hz, 2H), 7.83 (dd, J=8.5, 1.4 Hz,1H), 7.67 (d, J=8.5 Hz, 1H), 7.33 (bs, 1H), 7.16 (t, J=7.7 Hz, 1H), 7.03(bm, 3H), 4.03 (s, 2H), 2.21 (s, 3H).

Example 71

2-[4-(1,3-Dihydro-isoindole-2-sulfonyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide

A. 4-(1,3-Dihydro-isoindole-2-sulfonyl)-benzaldehyde. This compound wasprepared as described in Example 46 substituting isoindoline (117 mg,0.978 mmol) for benzylamine in Step A. The title compound was obtainedas a white solid, 253 mg (90%).

B.2-[4-(1,3-Dihydro-isoindole-2-sulfonyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide. This compound was prepared as described in Example 46substituting 4-(1,3-dihydro-isoindole-2-sulfonyl)-benzaldehyde (190 mg,0.662 mmol) for N-benzyl-4-formyl-benzenesulfonamide in Step B. Thetitle compound was obtained as a yellow powder, 122 mg (44%). HPLC(Method C): R_(t)=4.69. MS (ESI): mass calculated for C₂₂H₁₈N₄O₃S,418.5; m/z found, 419.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 8.41 (d,J=8.5 Hz, 2H), 8.07 (d, J=8.5 Hz, 1H), 8.03 (bs, 1H), 7.81 (bd, J=8.1Hz, 1H), 7.65 (bs, 1H), 7.33 (bs, 1H), 7.25 (m, 5H), 4.65 (s, 4H).

Example 72

2-[4-(2,3-Dihydro-indole-1-sulfonyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide

A. 4-(2,3-Dihydro-indole-2-sulfonyl)-benzaldehyde. This compound wasprepared as described in Example 46 substituting indoline (117 mg, 0.978mmol) for benzylamine in Step A. The title compound was obtained as atan solid, 250 mg (89%).

B.2-[4-(2,3-Dihydro-indole-2-sulfonyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide. This compound was prepared as described in Example 46substituting 4-(2,3-dihydro-indole-2-sulfonyl)-benzaldehyde (202 mg,0.703 mmol) for N-benzyl-4-formyl-benzenesulfonamide in Step B. Thetitle compound was obtained as a beige powder, 130 mg (44%). HPLC(Method C): R_(t)=4.80. MS (ESI): mass calculated for C₂₂H₁₈N₄O₃S,418.5; m/z found, 419.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 8.36 (d,J=8.2 Hz, 2H), 8.22 (s, 1H), 8.04 (m, 3H), 7.84 (d, J=8.4 Hz, 1H), 7.67(d, J=8.4 Hz, 1H), 7.54 (d, J=8.0 Hz, 1H), 7.36 (s, 1H), 7.20 (m, 2H),7.01 (m, 1H), 4.01 (t, J=8.2 Hz, 2H), 2.94 (t, J=8.1 Hz, 2H).

Example 73

(±)-2-[4-(1-Phenyl-ethylsulfamoyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide

A. (±)-4-Formyl-N-(1-phenyl-ethyl)-benzenesulfonamide. This compound wasprepared as described in Example 46 substituting (±)-α-methylbenzylamine(119 mg, 0.978 mmol) for benzylamine in Step A. The title compound wasobtained as a white solid, 223 mg (79%).

B.(±)-2-[4-(1-Phenyl-ethylsulfamoyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide. This compound was prepared as described in Example 46substituting (±) 4-Formyl-N-(1-phenyl-ethyl)-benzenesulfonamide (198 mg,0.686 mmol) for N-benzyl-4-formyl-benzenesulfonamide in Step B. Thetitle compound was obtained as a beige powder, 96 mg (33%). HPLC (MethodC): R_(t)=4.49. MS (ESI): mass calculated for C₂₂H₂₀N₄O₃S, 420.5; m/zfound, 421.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 8.39 (d, J=8.2 Hz,1H), 8.28 (d, J=8.5 Hz, 2H), 8.15 (bs, 1H), 7.86 (d, J=8.5 Hz, 3H), 7.75(bs, 1H), 7.40 (bs, 1H), 7.19 (m, 5H), 4.46 (q, J=7.1 Hz, 1H), 1.28 (d,J=6.9 Hz, 3H).

Example 74

(±)-2-[4-(1,2,3,4-Tetrahydro-naphthalen-1-ylsulfamoyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide

A. (±)4-Formyl-N-(1,2,3,4-tetrahydro-naphthalen-1-yl)-benzenesulfonamide, Thiscompound was prepared as described in Example 46substituting-(±)-1,2,3,4-tetrahydro-1-naphthylamine (144 mg, 0.978 mmol)for benzylamine in Step A. The title compound was obtained as a whitesolid, 210 mg (68%).

B.(±)-2-[4-(1,2,3,4-Tetrahydro-naphthalen-1-ylsulfamoyl)-phenyl]H-benzoimidazole-5-carboxylic-acid-amide.This compound was prepared as described in Example 46 substituting (±)4-formyl-N-(1,2,3,4-tetrahydro-naphthalen-1-yl)-benzenesulfonamide (209mg, 0.662-mmol) for N-benzyl-4-formyl-benzenesulfonamide in Step B. Thetitle compound was obtained as a beige powder, 94 mg (32%). HPLC (MethodC): R_(t)=4.80. MS (ESI): mass calculated for C₂₄H₂₂N₄O₃S, 446.5; m/zfound, 447.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 8.43 (d, J=8.5 Hz,2H), 8.24 (bm, 2H), 8.08 (d, J=8.5 Hz, 2H), 8.05 (m, 1H), 7.84 (d, J=8.4Hz, 1H), 7.72 (bm, 1H), 7.34 (bs, 1H), 7.09 (m, 4H), 4.51 (bd, J=3.4 Hz,1H), 2.65 (bm, 2H), 1.79 (bm, 1H), 1.61° (bm, 3H).

Example 75

2-{4-[(Thiophen-2-ylmethyl)-sulfamoyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide

A. 4-Formyl-N-thiophen-2-ylmethyl-benzenesulfonamide. This compound wasprepared as described in Example 46 substituting(2-aminomethyl)thiophene (111 mg, 0.978 mmol) for benzylamine in Step A.The title compound was obtained as a white solid, 201 mg (73%).

B.2-{4-[(Thiophen-2-ylmethyl)-sulfamoyl]-Phenyl}-1H-benzoimidazole-5-carboxylicacid amide. This compound was prepared as described in Example 46substituting 4-formyl-N-thiophen-2-ylmethyl-benzenesulfonamide (186 mg,0.662 mmol) for N-benzyl-4-formyl-benzenesulfonamide in Step B. Thetitle compound was obtained as a beige powder, 114 mg (42%). HPLC(Method C): R_(t)=4.40. MS (ESI): mass calculated for C₁₉H₁₆N₄O₃S₂,412.5; m/z found, 413.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 8.39 (d,J=8.5 Hz, 2H), 8.30 (bs, 1H), 8.15 (bs, 1H), 7.99 (d, J=8.5 Hz, 2H),7.85 (d, J=8.4 Hz, 1H), 7.67 (bm, 1H), 7.40 (dd, J=5.0, 1.3 Hz, 1H),7.36 (bs, 1H), 6.94 (d, J=2.4 Hz, 1H), 6.91 (dd, J=5.0, 3.5 Hz, 1H),4.29 (s, 2H).

Example 76

2-{4-[(Furan-2-ylmethyl)-sulfamoyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide

A. 4-Formyl-N-furan-2-ylmethyl-benzenesulfonamide. This compound wasprepared as described in Example 46 substituting furfurylamine (95 mg,0.978 mmol) for benzylamine in Step A. The title compound was obtainedas a white solid, 203 mg (78%).

B.2-{4-[(Furan-2-ylmethyl)-sulfamoyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide. This compound was prepared as described in Example 46substituting 4-formyl-N-furan-2-ylmethyl-benzenesulfonamide (176 mg,0.662 mmol) for N-benzyl-4-formyl-benzenesulfonamide in Step B. Thetitle compound was obtained as a beige powder, 118 mg (45%). HPLC(Method C): R_(t)=4.24. MS (ESI): mass calculated for C₁₉H₁₆N₄O₄S,396.4; m/z found, 397.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 8.36 (d,J=8.5 Hz, 2H), 8.22 (bs, 1H), 8.05 (bs, 1H), 7.94 (d, J=8.5 Hz, 2H),7.84 (d, J=8.3 Hz, 1H), 7.68 (bm, 1H), 7.49 (d, J=0.91 Hz, 1H), 7.35(bm, 1H); 6.30 (dd, J=3.0, 1.9 Hz, 1H), 6.20 (d, J=3.0 Hz, 1H), 4.10 (s,2H).

Example 77

2-{4-[(Pyridin-4-ylmethyl)-sulfamoyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide

A. 4-Formyl-N-pyridin-4-ylmethyl-benzenesulfonamide. This compound wasprepared as described in Example 46 substituting (4-aminomethyl)pyridine(106 mg, 0.978 mmol) for benzylamine in Step A. The title compound wasobtained as a yellow solid, 219 mg (81%).

B.2-{4-[(Pyridin-4-ylmethyl)-sulfamoyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide. This compound was prepared as described in Example 46substituting 4-formyl-N-pyridin-4-ylmethyl-benzenesulfonamide (190 mg,0.688 mmol) for N-benzyl-4-formyl-benzenesulfonamide in Step B. Thetitle compound was obtained as a beige powder, 88 mg (31%). HPLC (MethodC): R_(t)=3.57. MS (ESI): mass calculated for C₂₀H₁₇N₅O₃S, 407.5; m/zfound, 408.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 8.48 (m, 3H), 8.38(bd, J=6.2 Hz, 2H), 8.32 (bs, 1H), 8.05 (bm, 4H), 7.86 (m, 2H), 7.63(bm, 1H), 7.35 (bm, 1H), 7.30 (d, J=5.7 Hz, 2H), 4.14 (bd, J=5.6 Hz,2H).

Example 78

2-[4-((S)-Indan-1-ylsulfamoyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide

A. 4-Formyl-N-indan-(S)-1-yl-benzenesulfonamide. This compound wasprepared as described in Example 46 substituting S-(+)-1-aminoindane(130 mg, 0.978 mmol) for benzylamine in Step A. The title compound wasobtained as a white solid, 242 mg (82%).

B. 2-[4-(S)-Indan-1-ylsulfamoyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide. This compound was prepared as described in Example 46substituting 4-formyl-N-indan-(S)-1-yl-benzenesulfonamide (199 mg, 0.662mmol) for M benzyl-4-formyl-benzenesulfonamide in Step B. The titlecompound was obtained as a beige powder, 74 mg (26%). HPLC (Method C):R_(t)=4.68. MS (ESI): mass calculated for C₂₃H₂₀N₄O₃S, 432.5; m/z found,433.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 8.43 (d, J=8.3 Hz, 2H), 8.23(bm, 2H), 8.09 (d, J=8.3 Hz, 2H), 8.06 (m, 1H), 7.84 (d, J=8.3 Hz, 1H),7.69 (m, 1H), 7.35 (bs, 1H), 7.16 (m, 4H), 4.79 (bm, 1H), 2.82 (m, 1H),2.69 (m, 1H), 2.10 (m, 1H), 1.66 (m, 1H).

Example 79 Determination of Compound Inhibition of Human Cds1 Activity

For the determination of human Cds1 activity in the presence of Cds1inhibitory compounds, such compounds were incubated in an aqueousmixture at pH 7.4 containing 50 mM HEPES, 100 mM NaCl, 10 mM MgCl₂, 5 nMrecombinant human Cds1, 10 μM synthetic peptides substrateSGLYRSPSMPENLNRPR having an N-terminal biotin, 1 μM adenosinetriphosphate, 50 μCi/mL of [γ-³³P] adenosine triphosphate, and aprotease inhibitor mixture. The reaction mixtures were incubated at 37°C. for 3 h. The peptide substrate was captured from the reaction mixtureby incubating the reaction mixture with streptavidin conjugated toagarose beads and 50 mM adenosine triphosphate. The agarose beads werewashed repeatedly with a 0.1% solution of Tween®-20 inphosphate-buffered saline, pH 7.4. Enzyme activity at different Cds1inhibitory compound concentrations was determined by measuring theamount of radioactive phosphate bound to the substrate peptide byscintillation counting. Results are expressed as IC₅₀ in Table 1 below.

TABLE 1 Cds1 Inhibition Example IC₅₀ (nM) 1 55 2 66 3 64 4 43 5 33 6 437 7 8 11 9 34 10 7 11 17 12 13 13 36 14 39 15 38 16 240 17 32 18 192 1929 20 9 21 16 22 33 23 5 24 4 25 71 26 8 27 7 28 13 29 23 30 47 31 9 32164 33 98 34 42 35 4 36 5 37 5 38 12 39 26 40 171 41 3 42 5 43 264 44113 45 38 46 56 47 112 48 150 49 66 50 99 51 290 52 182 53 77 54 54 5549 56 18 57 170 58 40 59 1100 60 42 61 40 62 80 63 14 64 272 65 114 6641 67 45 68 42 69 42 70 50 71 9 72 18 73 181 74 16 75 19 76 37 77 134 7810

Example 80 Determination of the Effect of Cds1 Inhibitory Compounds onRadiation-Induced Apoptosis in Isolated Primary Cells

Spleen cells were isolated from C57/BL6 mice as follows: spleens weredisrupted by grinding between two frosted glass slides, and cells werepassed through a cell strainer. Erythrocytes were lysed by incubation inammonium chloride solution followed by careful washing of cells inisotonic medium. The spleen cells were plated in 60 mm petri dishes at5×10⁶ cells/mL in RPMI medium containing 10% fetal calf serum and Cds1inhibitor. One hour after plating of cells with compound, the cells weredosed with 0.5-1 Gy from a ¹³⁷Cs γ-radiation source. Determination ofapoptotic cells by Annexin V staining was performed using the AnnexinV-FITC Apoptosis Detection Kit™ (Cat# PF032 Oncogene Research Products)according to the manufacturer's instructions. Briefly, 6-24 h afterirradiation, the cells were washed with buffered isotonic salt solutionand suspended at 1×10⁶ cells/mL in binding buffer (10 mM. HEPES pH 7.4,150 mM NaCl, 2.5 mM CaCl₂, 1 mM MgCl₂, 4% bovine serum albumin)containing 80 ng/mL Annexin V labelled with FITC and 0.4 μg/mL anti-B220antibody labelled with allophycocyanin. The cells were then pelleted andresuspended in binding buffer containing 0.6 μg/mL propidium iodide. Thestained cells were analyzed on a FACS machine (Fluorescence ActivatedCell Sorter™, Becton Dickinson). The fraction of viable, non-apoptoticcells was determined by quantifying the number of cells that did notstain with propidium iodide or Annexin V versus the total number ofcells. Fractions of non-apoptotic B-cells or total cells were determinedseparately based on staining with the B220 antibody mentioned above.

Example 81 Determination of Effect of Cds1 Inhibitors onRadiation-Induced Caspase Activity in Human C₄ ⁺ T-Cells

Human C₄ ⁺ T-cells were isolated from the blood of healthy donors asfollows. Whole heparinized blood was layered over Ficoll-Paque (AmershamPharmacia Biotech, Uppsala, Sweden) and centrifuged 20 min at 560 g.Mononuclear cells were harvested and subjected to positive selectionwith anti-human CD4-coated MACS MicroBeads (Miltenyi, Auburn, Calif.).Purified CD₄ ⁺ T-cells were transferred to growth medium (RPMI with 10%fetal calf serum, 50% IU/mL penicillin and 50 μg/mL streptomycin). Thecells were dispensed to wells of 96-well tissue culture plates at200,000 cells/well. Either a Cds1 inhibitory compound in DMSO or thesame volume of vehicle was added to each well. The reaction mixtureswere incubated at 37° C. for 1 h, exposed to 10 Gy of γ-radiation, andthen incubated for 24 h. The C₄ ⁺ T-cells were harvested bycentrifugation and lysed to release caspase-3. Caspase-3 and caspase-7specific fluorogenic peptide substrateAcetyl-Asp-Glu-Val-Asp-(7-amino-4-methyl-coumarin) was added to eachsample (final concentration=100 μM). Three hours after the addition ofpeptide, the caspase activity of each sample was determinedfluorometrically using a Millipore Cytofluor fluorescent plate reader(λ_(ex)=360 nm, λ_(em)=460 nm).

Example 82 Determination of the Effect of Cds1 Inhibitory Compounds onRadiation-Induced Apoptosis in Human CD₄ ⁺ T-Cells

Human CD₄ ⁺ T-cells were isolated from the blood of healthy donors andcultured as described in Example 54. The cells were dispensed to wellsof 96-well tissue culture plates at 200,000 cells/well. Either a Cds1inhibitory compound in DMSO or the same volume of vehicle was added toeach well. The reaction mixtures were incubated at 37° C. for 1 h,exposed to 10 Gy of γ-radiation, and then incubated for 24 h.Determination of apoptotic cells by Annexin V staining was performed asdescribed in Example 53.

Example 83 Determination of the Effect of Cds1 Inhibitory Compounds onRadiation-Induced Apoptosis in Splenocytes in vivo

Female C57/BL mice, 6-8 weeks of age, are dosed by oral gavage or byinjection with Cds1 inhibitory compound before and at regular intervalsafter radiation exposure. One to three hours after first compound dose,the animals are irradiated with γ-rays administered to the whole animalat a dose between 0.5 and 4 Gy. At times between 4 and 24 h afterirradiation, the animals are sacrificed, and the tissues of interest areexcised. Cell apoptosis is quantified using Annexin V staining asdescribed in Example 53. Apoptosis can be studied in a variety oftissues. In some cases other methods for quantification of apoptosisthan the method described in Example 53 may be more appropriate. Thus,apoptosis can also be determined by detection of DNA degradation byTUNEL staining, as described by Darzynkiewicz and Bedner (In Analysis ofApoptotic Cells by Flow and Laser Scanning Cytometry, Reed, J. C., Ed.;Methods of Enzymology, Vol. 322; Academic Press: San Diego, 2000;18-39). Briefly; cells or tissues are fixed with formaldehyde andpermeabilized with ethanol, and DNA ends are then labelled by attachingnucleotide derivatives such as BrdUTP using the enzyme terminaldeoxynucleotidyl transferase. DNA ends can then be detected byincubating the cells or tissues with fluorescently-labelled antibodiesreactive with BrdU. Quantification can be done by laser scanningcytometry, by visual microscopical examination or by FACS.

F. OTHER EMBODIMENTS

The features and advantages of the invention are apparent to one ofordinary skill in the art. Based on this disclosure, including thesummary, detailed description, background, examples, and claims, one ofordinary skill in the art will be able to make modifications andadaptations to various conditions and usages. These other embodimentsare also within the scope of the invention.

1. A compound of formula (I):

wherein W is —COOH, or —(CO)NH₂; Q is CH; R_(a) and R_(b) areindependently selected from —H and halogen; R_(c) is absent or isindependently selected from the group consisting of —OH, —CF₃,—C₁₋₄alkyl, —OC₁₋₄alkyl, —NO₂ and halo; Z is >CR_(d)OR_(e); R_(d) is —H;R_(e) is independently selected from the group consisting of —H andC₁₋₄alkyl; A is phenyl, optionally mono-, di- or tri-substituted withR_(p); R_(p) is selected from the group consisting of —OH, —C₁₋₆alkyl,—OC₁₋₆alkyl, —C₃₋₆cycloalkyl, —OC₃₋₆cycloalkyl, —CN, —NO₂,—N(R_(y))R_(z) (wherein R_(y) and R_(z) are independently selected from—H or —C₁₋₆alkyl, or may be taken together with the nitrogen ofattachment to form an otherwise aliphatic hydrocarbon ring, said ringhaving 5 to 7 members, optionally having one carbon replaced with >O,═N—, >NH or >N(C₁₋₄alkyl) and optionally having one or two unsaturatedbonds in the ring), —(C═O)N(R_(y))R_(z), —(N—R_(t))COR_(t) (whereinR_(t) is independently —H or —C₁₋₆alkyl), —(N—R_(t))SO₂C₁₋₆alkyl,—(C═O)C₁₋₆alkyl, —(S═(O)_(n))—C₁₋₆alkyl (wherein n is selected from 0, 1or 2), —SO₂N(R_(y))R_(z), —SCF₃, halo, —CF₃, —OCF₃, —COOH,—C₁₋₆alkylCOOH, —COOC₁₋₆alkyl and —C₁₋₆alkylCOOC₁₋₆alkyl; andenantiomers, diastereomers and pharmaceutically acceptable salts, estersor amides thereof.
 2. The compound of claim 1 wherein W is —(CO)NH₂. 3.The compound of claim 1 wherein R_(a) and R_(b) are —H, —Cl or —F. 4.The compound of claim 1 wherein R_(a) is —H and R_(b) is —Cl or —F. 5.The compound of claim 1 wherein R_(a) and R_(b) are —H.
 6. The compoundof claim 1 wherein R_(c) is absent or is selected from the groupconsisting of —OH, —CH₃, —CH₂CH₃, —F, —Cl, —Br, —I, —CF₃ and —OCH₃. 7.The compound of claim 1 wherein R_(c) is selected from the groupconsisting of —F, —Cl, —CH₃ and —OCH₃.
 8. The compound of claim 1wherein R_(c) is absent.
 9. The compound of claim 1 wherein R_(e) isselected from the group consisting of —H, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃,—CH₂CH₂CH₂CH₃.
 10. The compound of claim 1 wherein R_(e) is selectedfrom the group consisting of —H, —CH₃ and —CH₂CH₃.
 11. The compound ofclaim 1 wherein R_(e) is —H or —CH₃.
 12. The compound of claim 1 whereinZ is selected from the group consisting of >CHOH and >CHOC₁₋₄alkyl. 13.The compound of claim 1 wherein Z is >CHOR_(e).
 14. The compound ofclaim 1 wherein A, including the R_(p) substituent, is selected from thegroup consisting of phenyl, 4-chloro phenyl, 4-methyl-3-chloro phenyl,4-chloro-3-trifluoromethyl phenyl, 3,4-dichloro phenyl,3-chloro-4-fluoro phenyl, 2-fluoro-5-trifluoromethyl, 4-chloro-3-fluorophenyl, 3,4-dimethyl phenyl, 2-napthyl, 4-trifluoromethyl phenyl,4-bromo phenyl, 4-fluoro-3-methyl phenyl, 3-chloro phenyl,5-chloro-2-methyl phenyl, 3-trifluoromethyl phenyl, 4-methoxy phenyl,4-methyl phenyl, 3,4-dimethyl phenyl, 2-fluoro-3-trifluoromethyl phenyl,2-chloro-4-methyl phenyl, 4-ethyl phenyl, 4-fluoro phenyl, 3,4-dimethoxyphenyl, 3,4-dimethoxy-5-bromo phenyl, 3-(dimethylamino) phenyl, 4-nitrophenyl, 4-cyano phenyl, 2-methoxy-4-methyl phenyl, 4-trifluoromethoxyphenyl, 2-chloro phenyl, 4-morpholino phenyl, 3-chloro phenyl,2,3-dichloro phenyl, benzo[1,3]dioxolyl, benzo[1,4]dioxinyl, 4-aminophenyl, 4-hydroxy phenyl, 4-bromo-3-hydroxy phenyl, 4-chloro-2-hydroxyphenyl, 4-chloro-3-hydroxy phenyl, 2,4-dichloro phenyl,4-bromo-3-methoxy phenyl and 4-iodo phenyl.
 15. The compound of claim 1wherein A, including the R_(p) substituent, is selected from the groupconsisting of phenyl, 4-chlorophenyl, 4-methylphenyl, 4-methoxyphenyl,4-chloro-3-trifluoromethylphenyl, 3-bromo-4,5-dimethoxyphenyl,3,4-dichlorophenyl, 3,4-dimethylphenyl, 4-ethylphenyl, 2-chlorophenyl,2,4-dichlorophenyl, 2-methoxyphenyl, 2-methylphenyl, and 3-methylphenyl.16. The compound of claim 1 wherein R_(p) is selected from the groupconsisting of —OH, —CH₃, —CH₂CH₃, —OCH₃, —OCH₂CH₃, —OCH(CH₃)₂,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, —Ocyclopentyl,—Ocyclohexyl, —CN, —NO₂, —C(O)NH₂, —C(O)N(CH₃)₂, —C(O)NH(CH₃), —NHCOCH₃,—NCH₃COCH₃, —NHSO₂CH₃, —NCH₃SO₂CH₃, —C(O)CH₃, —SOCH₃, —SO₂CH₃, —SO₂NH₂,—SO₂NHCH₃, —SO₂N(CH₃)₂, —SCF₃, —F, —Cl, —Br, I, —CF₃, —OCF₃, —COGH,—COOCH₃, —COOCH₂CH₃, —NH₂, —NHCH₃, —N(CH₃)₂, —N(CH₂CH₃)₂,—NCH₃(CH(CH₃)₂), imidazolidin-1-yl, 2-imidazolin-1-yl, pyrazolidin-1-yl,piperidin-1-yl, 2- or 3-pyrrolin-1-yl, 2-pyrazolinyl, morpholin-4-yl,thiomorpholin-4-yl, piperazin-1-yl, pyrrolidin-1-yl, homopiperidin-1-yl.17. The compound of claim 1 wherein R_(p) is selected from the groupconsisting of —H, —OH, —OCH₃, OCF₃, CH₃, CH₂CH₃, CF₃, —F, —Cl, —Br, —I,NH₂, N(CH₃)₂, morpholin-4-yl, —NO₂, —CN, —C(O)NH₂, —COOH, —NHSO₂CH₃,—SO₂NH₂.
 18. The compound of claim 1 selected from the group consistingof: 2-[4-(Hydroxy-phenyl-methyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide;2-{4-[(4-Chloro-phenyl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide;2-[4-(Hydroxy-p-tolyl-methyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide;2-{4-[Hydroxy-(4-methoxy-phenyl)-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide;2-[4-(Hydroxy-naphthalen-2-yl-methyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide;2-{4-[(4-Chloro-3-trifluoromethyl-phenyl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide2-{4-[(3-Bromo-4,5-dimethoxy-phenyl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide;2-{4-[(3,4-Dichloro-phenyl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide;2-{4-[(3,4-Dimethyl-phenyl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide;2-{4-[(4-Ethyl-phenyl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide; 2-[4-(Benzo[1,3]dioxol-5-yl-hydroxy-methyl)-phenyl]-1H-benzoimidazole-5-carboxylic acidamide;2-{4-[(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide2-[4-(Hydroxy-quinolin-3-yl-methyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide;2-[4-(Hydroxy-pyridin-4-yl-methyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide;2-[4-(Cyclohexyl-hydroxy-methyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide;2-[4-(Methoxy-phenyl-methyl)-phenyl]-1H-benzoimidazole-5-carboxylic acidamide; substituted phenyl;2-{4-[Hydroxy-(tetrahydro-pyran-4-yl)-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide;2-[4-(Hydroxy-thiophen-2-yl-methyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide; 2-{4-[(6-Chloro-benzo[1,31dioxol-5-yl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylic acidamide;2-{4-[(2-Chloro-phenyl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide;2-{4-[(2,4-Dichloro-phenyl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide;2-{4-[Hydroxy-(2-methoxy-phenyl)-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide;2-[4-(Hydroxy-o-tolyl-methyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide.
 19. The compound of claim 1 selected from the groupconsisting of:2-{4-[(2,4-Dichloro-phenyl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide;2-{4-[Hydroxy-(1-methyl-1H-imidazol-2-yl)-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide;2-{4-[(5-Chloro-thiophen-2-yl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide;2-[4-(Hydroxy-piperidin-4-yl-methyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide;2-{4-[Hydroxy-(tetrahydro-thiopyran-4-yl)-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide.
 20. The compound of claim 1 selected from the groupconsisting of:2-[4-(Hydroxy-phenyl-methyl)-phenyl]-1H-benzoimidazole-5-carboxylic acidamide;2-{4-[(4-Chloro-phenyl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide;2-[4-(Hydroxy-p-tolyl-methyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide;2-{4-[Hydroxy-(4-methoxy-phenyl)-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide;2-[4-(Hydroxy-naphthalen-2-yl-methyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide;2-{4-[(4-Chloro-3-trifluoromethyl-phenyl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide;2-{4-[(3,4-Dichloro-phenyl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide;2-{4-[(3,4-Dimethyl-phenyl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide;2-{4-[(4-Ethyl-phenyl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide; 2-[4-(Benzo[1,31dioxol-5-yl-hydroxy-methyl)-phenyl]-1H-benzoimidazole-5-carboxylic acidamide;2-[4-(Hydroxy-quinolin-3-yl-methyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide.
 21. The compound of claim 1 selected from the groupconsisting of2-{4-[(4-Chloro-phenyl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide;2-[4-(Hydroxy-naphthalen-2-yl-methyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide;2-{4-[(4-Chloro-3-trifluoromethyl-phenyl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide;2-{4-[(3,4-Dichloro-phenyl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide;2-{4-[(3,4-Dimethyl-phenyl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide;2-[4-(Hydroxy-quinolin-3-yl-methyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide.
 22. The compound of claim 1 selected from the groupconsisting of:2-[4-(Hydroxy-phenyl-methyl)-phenyl]-1H-benzoimidazole-5-carboxylic acidamide;2-{4-[(4-Chloro-phenyl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide;2-[4-(Hydroxy-p-tolyl-methyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide;2-{4-[Hydroxy-(4-methoxy-phenyl)-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide;2-[4-(Hydroxy-naphthalen-2-yl-methyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide;2-{4-[(4-Chloro-3-trifluoromethyl-phenyl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide;2-{4-[(3-Bromo-4,5-dimethoxy-phenyl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide;2-{4-[(3,4-Dichloro-phenyl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide;2-{4-[(3,4-Dimethyl-phenyl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide;2-{4-[(4-Ethyl-phenyl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide; 2-[4-(Benzo[1,31dioxol-5-yl-hydroxy-methyl)-phenyl]-1H-benzoimidazole-5-carboxylic acidamide;2-{4-[(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide;2-[4-(Hydroxy-quinolin-3-yl-methyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide;2-[4-(Hydroxy-pyridin-4-yl-methyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide;2-[4-(Cyclohexyl-hydroxy-methyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide;2-{4-[Hydroxy-(tetrahydro-pyran-4-yl)-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide;2-[4-(Hydroxy-thiophen-2-yl-methyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide; 2-{4-[(6-Chloro-benzo[1,31dioxol-5-yl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylic acidamide;2-{4-[(2-Chloro-phenyl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide;2-{4-[(2,4-Dichloro-phenyl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide;2-{4-[Hydroxy-(2-methoxy-phenyl)-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide;2-[4-(Hydroxy-o-tolyl-methyl)-phenyl]-1H-benzoimidazole-5-carboxylicacid amide; and2-{4-[(2,4-Dichloro-phenyl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylicacid amide.
 23. A pharmaceutical composition comprising apharmaceutically acceptable carrier and a therapeutically effectiveamount of a compound of the formula:

wherein W is —COOH, or —(CO)NH₂; Q is CH; R_(a) and R_(b) areindependently selected from —H and halogen; R_(c) is absent or isindependently selected from the group consisting of —OH, —CF₃,—C₁₋₄alkyl, —OC₁₋₄alkyl, —NO₂ and halo; Z is >CR_(d)OR_(e); R_(d) is —H;R_(e) is independently selected from the group consisting of —H and—C₁₋₄alkyl; A is phenyl, optionally mono-, di- or tri-substituted withR_(p); R_(p) is selected from the group consisting of —OH, —C₁₋₆alkyl,—OC₁₋₆alkyl, —C₃₋₆cycloalkyl, —OC₃₋₆cycloalkyl, —CN, —NO₂,—N(R_(y))R_(z) (wherein R_(y) and R_(z) are independently selected from—H or —C₁₋₆alkyl, or may be taken together with the nitrogen ofattachment to form an otherwise aliphatic hydrocarbon ring, said ringhaving 5 to 7 members, optionally having one carbon replaced with >O,═N—, >NH or >N(C₁₋₄alkyl) and optionally having one or two unsaturatedbonds in the ring), —(C═O)N(R_(y))R_(z), —(N—R_(t))COR_(t) (whereinR_(t) is independently —H or —C₁₋₆alkyl), —(N—R_(t))SO₂C₁₋₆alkyl,—(C═O)C₁₋₆alkyl, —(S═(O)_(n))—C₁₋₆alkyl (wherein n is selected from 0, 1or 2), —SO₂N(R_(y))R_(z), —SCF₃, halo, —CF₃, —OCF₃, —COOH,—C₁₋₆alkylCOOH, —COOC₁₋₆alkyl and —C₁₋₆alkylCOOC₁₋₆alkyl; andenantiomers, diastereomers and pharmaceutically acceptable salts, estersor amides thereof.